Drug eluting stents with prolonged local elution profiles with high local concentrations and low systemic concentrations

ABSTRACT

A drug eluting stent can include a stent body having a polymeric coating with a lipophilic and/or hydrophilic element. A drug that has a bioactivity that inhibits cell proliferation can be disposed in the polymeric coating. The drug can be present in the polymer at an amount greater than or equal to about 150 ug/cm 2 . The polymeric coating and drug are configured to cooperate so as to form a diffusion pathway with tissue when the stent is disposed in a body lumen such that the drug preferentially diffuses into the tissue over a body fluid passing through the body lumen such that a maximum systemic blood concentration of the drug is less than about 40 ng/ml.

CROSS-REFERENCE TO RELATED APPLICATIONS

This U.S. patent application claims benefit of U.S. Provisional PatentApplication having Ser. No. 60/915,355, filed on May 1, 2007, whichProvisional Patent Application is incorporated herein by specificreference in its entirety.

BACKGROUND OF THE INVENTION

1. The Field of the Invention

The present invention generally relates to a polymer/drug-coated stent.More particularly, the polymer/drug-coated stent is configured have thedrug disposed within the polymer coating in a manner that controls theelution of the drug so as to preferentially deliver the drug intovascular tissue adjacent to the stent while maintaining a sufficientlylow systemic concentration range of the drug below a specified value.

2. The Relevant Technology

Endovascular techniques have become important adjuncts in the managementof atherosclerotic occlusive disease. Once amendable only to opensurgical revascularization, a wide range of lesions can now beapproached percutaneously without the need for incision and dissection.Endovascular interventions within coronary arteries are particularlyeffective, and have become the preferred method of treatment for themajority of patients with occlusive syndromes of the coronarycirculation.

Endovascular intervention in the peripheral circulation has proven moreproblematic. Although generally effective in the relatively large inflowarteries of the extracranial cerebrovascular, renal and iliaccirculations, endovascular manipulation of the infrainguinal arteries istechnically more challenging, and the outcome less durable.

A variety of approaches have been suggested to enhance patency duringperipheral endovascular intervention including pharmacotherapy,stenting, cryoplasty, cutting balloon angioplasty, radiationbrachytherapy and atherectomy. The most popular to date is stenting, asresults from a recent randomized clinical trial suggest that routinenitinol stenting enhances both angiographic and clinical resultsfollowing balloon angioplasty, especially in patients with long, complexocclusive lesions of the superficial femoral artery (SFA).

However, the long-term results of stenting in the peripheral vasculaturecontinue to be plagued by restenosis. Restenosis, mediated by thepathological process of neointimal hyperplasia, complicates roughly 40%of all peripheral vascular interventions after one year, leading arecent international consensus panel of cardiologists, vascularsurgeons, and interventional radiologists to suggest that the currentstate-of-the-art of SFA stenting results in only 62% patency after oneyear.

As significant enhancements in stented arterial patency have beenachieved in the coronary circulation through the use of drug-elutingstents (DES), it was natural that this technology would be eventuallyapplied to the peripheral circulation. Several small series have beenpublished that suggest that drug-eluting stents designed for thecoronary arteries might also be efficacious in limiting restenosis andimproving patency in the infrapopliteal arteries. Similarly, thehypothesis that drug-eluting stents might also be efficacious in thelarger and more complex SFA was previously addressed. Also,self-expanding drug-eluting stents utilized a nitinol platform, wasloaded with 90 μg sirolimus/cm² stent area using a 5-10 μm co-polymermatrix for total drug load ˜1 mg per 80 mm stent (i.e., stent 1), anddelivered its drug load over a period of about seven days. A total of 93patients were enrolled in combined clinical trials for the stent.Unfortunately, neither trial achieved its primary endpoint of areduction in restenosis and, even after four years, there was nodifference in any metric comparing patients treated with the barenitinol stent vs. the sirolimus-eluting nitinol stent. The developmentof the this drug-eluting stent was terminated, and no drug-eluting stentis yet available for clinical use anywhere in the world.

In retrospect, some have hypothesized that the failure of thedrug-eluting stent design (e.g., stent 1) was in its inadequate drugdelivery. As stated, Stent 1 was loaded with 90 μg sirolimus/cm² stentarea which was lower that one successful sirolimus-eluting coronarystent (e.g., stent 2), which had 140 μg sirolimus/cm² stent area.Moreover, stent 1 released sirolimus over about seven days, which isconsiderably shorter than the 30 day release of stent 2, both beinginsufficient in duration for intended therapeutic purposes. As coronarystents with short elution profiles are generally less efficacious thantheir longer-eluting counterparts, it was perhaps not surprising thatstent 1 failed to demonstrate efficacy in reducing restenosis.

A second observation made from the aforementioned studies was that largeperipheral drug-eluting stents with relatively high drug loads and fastelution can subsequently generate significant levels of drug in thesystemic circulation. These systemic levels of drug can be consideredunsafe and may have adverse side effects. In any event, high systemiclevels of drug is not advantageous and may counteract the intendedtherapy. Some coronary drug-eluting stents, with their minimal drugloads (˜100 μg), generate little in the way of systemic drugconcentration; whole blood levels exceeding 2 ng/ml are rarely observed.In contrast, large peripheral drug-eluting stents carry drug loads inthe milligram (mg) range, and thereby have extremely fast drug elutionthat increases systemic concentration of the drug and may result inadverse systemic drug exposure. Such was the case in the aforementionedtrial in which treated patients exhibited a mean systemic sirolimusconcentration of 20.4±10.0 ng/ml one hour after stenting, including onepatient with a peak concentration of 35.5 ng/ml sirolimus afterreceiving three 80 mm stents configured as stent 1. These concentrationsare measurably higher than the 9 ng/ml trough concentration observed inkidney transplant recipients receiving the usual oral dose of sirolimusof 2 mg per day. These high systemic drug concentrations has been deemedexcessive in terms of adverse effects that may occur by long-termexposure to high systemic drug concentrations.

Lastly, a final unexpected consequence of the aforementioned trial, anda possible reason for its failure, was the observation that the stentplatform was prone to fracture. Of the 93 patients enrolled, stentfracture was found in 18% at six months, including single strutfractures in eight patients, multiple strut fractures in four patients,complete transverse linear stent separations in two patients, andtransverse linear fractures with stent displacement in two patients. Ithas been suggested that stent fracture may create a nidus forrestenosis, given the documented association between strut fracture,restenosis and therapeutic failure. Indeed, the reported frequency ofstrut fracture following peripheral stenting is surprisingly high,including one retrospective clinical study demonstrating a fracture rateof 65%.

BRIEF SUMMARY OF THE INVENTION

Generally, the present invention includes a polymer/drug-coated stent.The polymer/drug-coated stent is configured have the drug disposedwithin the polymer coating in a manner that controls the elution of thedrug so as to preferentially deliver the drug into vascular tissueadjacent to the stent while maintaining a sufficiently low systemicconcentration of the drug.

In one embodiment, the present invention can include a drug elutingstent that has a stent body, a polymeric coating, and a lipophilic drug.The polymeric coating can have a lipophilic element and be disposed onthe stent body. The lipophilic drug can have a bioactivity that inhibitscell proliferation, and can be disposed in the polymeric coating.However, any lipophilic drug with any activity can be used for thetreatment of an appropriate condition.

In one embodiment, the present invention can include a drug elutingstent that has a stent body, a polymeric coating, and a hydrophilicdrug. The polymeric coating can have a hydrophilic element and bedisposed on the stent body. For example, the hydrophilic drug can have abioactivity that inhibits cell proliferation, and can be disposed in thepolymeric coating. However, any hydrophilic drug with any activity canbe used for the treatment of an appropriate condition.

In one embodiment, the present invention can include a drug elutingstent that has a stent body, a polymeric coating, and a amphipathic drughaving both hydrophilic and lipophilic components. The polymeric coatingcan have a hydrophilic and/or hydrophilic element and be disposed on thestent body. For example, the amphipathic drug can have a bioactivitythat inhibits cell proliferation, and can be disposed in the polymericcoating. However, any amphipathic drug with any activity can be used forthe treatment of an appropriate condition.

In one embodiment, the drug can be present in the polymer at an amountfrom about 10 ug/cm² (micrograms drug/area of stent) to about 2000ug/cm², more preferably from about 100 ug/cm² to about 1000 ug/cm², andmost preferably from about 200 ug/cm² to about 500 ug/cm².

In one embodiment, the drug per area can be greater or equal to about150 ug/cm², more preferably greater or equal to about 175 ug/cm², evenmore preferably greater or equal to about 200 ug/cm², and mostpreferably greater or equal to about 225 ug/cm².

In one embodiment, the amount of drug on the stent can be described asthe total amount of drug per stent. Accordingly, the amount of drug perstent can be from about 0.5 mg to about 12 mg, more preferably fromabout 0.75 mg to about 10 mg, and most preferably from about 1 mg toabout 5 mg.

The polymeric coating and drug are configured to cooperate so as to forma lipophilic diffusion pathway with tissue when the stent is disposed ina body lumen such that the lipophilic drug preferentially diffuses intothe tissue over a body fluid passing through the body lumen such that amaximum systemic blood concentration of the drug is less than or about30 ng/ml, more preferably less than or about 20 ng/ml, and mostpreferably less than or about 10 ng/ml.

In one embodiment, the stent body is comprised of a superelastic alloy,such as nitinol. The nitinol can have an ethylenevinylalcohol copolymercoating disposed thereon. A therapeutically effective amount ofeverolimus can be disposed in the polymeric coating so as to be presentat an amount greater than or equal to about 150 ug/cm². The polymercoating and everolimus are configured so as to cooperate to form alipophilic diffusion pathway with tissue when the stent is disposed in abody lumen such that the everolimus preferentially diffuses into thetissue over a body fluid passing through the body lumen and such that amaximum systemic blood concentration of everolimus is less than about 40ng/ml.

In one embodiment, the present invention includes a method of inhibitingocclusion, stenosis, restenosis, or cell over-proliferation in a bodylumen in a subject. Such a method includes providing a stent asdescribed herein and deploying the drug eluting stent into the bodylumen.

In one embodiment, the present invention includes a method ofmanufacturing a stent in accordance with the present invention. Such amethod includes preparing a stent body, preparing a polymer/drugsolution, and applying the polymer/drug solution to the stent body.Alternatively, the polymer and drug can be applied to the stentseparately. Additionally, a polymeric topcoat can be applied over thepolymeric coating that has the drug.

In one embodiment, the drug eluting stent produces a systemic bloodconcentration of the drug that in turn produces at least one of thefollowing: a maximum kidney concentration of less than or about 50 ng/g,more preferably less than or about 40 ng/g, and most preferably lessthan or about 30 ng/g; a maximum lung concentration of less than orabout 45 ng/g, more preferably less than or about 35 ng/g, and mostpreferably less than or about 25 ng/g; a maximum muscle concentration ofless than or about 35 ng/g, less than or about 30 ng/g, and mostpreferably less than or about 25 ng/g; a maximum liver concentration ofless than or about 30 ng/g, more preferably less than or about 25 ng/g,and most preferably less than or about 17 ng/g; or a maximum spleenconcentration of less than or about 35 ng/g, more preferably less thanor about 30 ng/g, and most preferably less than or about 25 ng/g.

In one embodiment, the maximum systemic blood concentration of the drugis less than about 4 ng/ml per milligram of total drug on the stent.

In one embodiment, the maximum systemic blood concentration of the drugis less than about 15 pg/ml per millimeter of stent length.

In one embodiment, the stent is characterized by at least one of thefollowing: the drug is present at greater than or about 3.8 mg; themaximum systemic blood concentration is from about 0.6 ng/ml to about 15ng/ml; the drug is present at greater than or about 7.5 mg; the maximumsystemic blood concentration is from about 1.5 ng/ml to about 30 ng/ml;the drug is present at greater than or about 10 mg; or the maximumsystemic blood concentration is from about 2 ng/ml to about 40 ng/ml.

In one embodiment, the polymeric coating ranges from about 2 um to about50 um. Optionally, the polymeric coating includes a primer layerdisposed on the stent body, a drug-loaded layer disposed on the primerlayer, and a topcoat layer disposed on the drug-loaded layer so as tocontrol elution of the drug. Accordingly, the polymeric coating ischaracterized by at least one of the following: the primer layer beingfrom 1% to about 20% of the total coating thickness; the drug-loadedlayer being from about 25% to about 90% of the total coating thickness;or the topcoat being from about 5% to about 50% of the total coatingthickness.

In one embodiment, the stent body is a superelastic alloy such asnitinol. This can be linear superelastic and non-linear superelasticnitinol.

In one embodiment, the drug is a rapamycin analog such as everolimus orzotarolimus.

In one embodiment, the polymer coating and/or polymeric topcoat is anethylenevinylalcohol copolymer.

These and other embodiments and features of the present invention willbecome more fully apparent from the following description and appendedclaims, or may be learned by the practice of the invention as set forthhereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

To further clarify the above and other advantages and features of thepresent invention, a more particular description of the invention willbe rendered by reference to specific embodiments thereof which areillustrated in the appended drawings. It is appreciated that thesedrawings depict only typical embodiments of the invention and aretherefore not to be considered limiting of its scope. The invention willbe described and explained with additional specificity and detailthrough the use of the accompanying drawings in which:

FIG. 1 is a planar side view of a portion of an embodiment of anexemplary endoprosthesis in accordance with the present invention.

FIG. 2A is a graph illustrating the percent of drug eluted from a drugeluting stent.

FIG. 2B is a graph illustrating the arterial tissue drug concentrationobtained from a drug eluting stent.

FIG. 3 includes a graph illustrating everolimus blood concentrationafter drug eluting stent implantation.

FIGS. 4A-4C include photographs of vessels (FIGS. 4A and 4C) andcross-sections (FIGS. 4B and 4D) of vessels at 90 days after drugeluting stent (DES) (FIGS. 4A and 4B) and bare metal stent (BMS) (FIGS.4C and 4D) implantation.

FIGS. 5A-5C include schematic representations of a stent delivery system(FIG. 5A) and a method of delivering the stent into a body lumen (FIG.5B) with the stent delivery system of FIG. 5A.

FIGS. 6A-6C include schematic representations of a lumen filter (FIG.6A) that is deployed into a body lumen with a lumen filter deliverysystem (FIG. 6B) and a method of delivering the stent into a body lumen(FIG. 6C) with the lumen filter delivery system of FIG. 6B.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Generally, the present invention includes drug eluting implantablemedical devices such as endoprostheses, vena cava filters, embolicprotection filters, and the like that are configured with controlleddrug delivery profiles that allow for enhanced drug delivery into thelumen tissue adjacent to the implantable medical device and thatinhibits drug delivery into the systemic blood circulation. Thepreferential drug delivery into the lumen tissue can be facilitated by ahydrophobic component being included in a coating on the medical device(e.g., stent or vena cava filter) that is in contact with the lumentissue. The hydrophobic components of the tissue cooperate with thehydrophobic component of the coating so as to facilitate preferentialdiffusion of a hydrophilic drug into the tissue over into systemicblood. Similarly, the drug can be hydrophilic or amphipathic by havingboth lipophilic and hydrophilic portions. The polymer can include ahydrophilic component for the hydrophilic drug, and hydrophilic and/orhydrophobic components for the lipophilic, hydrophilic, or amphipathicdrugs.

As used herein, the term “micro” has been abbreviated with the standardsymbol “μ” or “u” for simplicity.

I. Drug Eluting Endoprosthesis

In accordance with the present invention, a drug eluting endoprosthesiscan be provided for improved drug delivery within a body lumen of ahuman or other animal. Examples of drug eluting endoprostheses caninclude stents, filters, grafts, valves, occlusive devices, trocars,aneurysm treatment devices, or the like. Additionally, the drug elutingendoprosthesis can be configured for a variety of intralumenalapplications, including vascular, coronary, biliary, esophageal,urological, gastrointestinal, or the like.

Additional medical device embodiments, i.e. vena cava filter that can beimplanted in the vena cava to elute drug over time. The device becomes asystemic drug release device instead of a device to treat an area ofstenosis. The drug release device could replace daily pills forindividuals in need of the therapy provided by the drug, such astransplant patients.

Generally, an endoprosthesis of the present invention can include atleast a first set of interconnected strut elements that cooperativelydefine an annular element. A strut element can be more generallydescribed as an endoprosthetic element, wherein all well-knownendoprosthetic elements can be referred to here as a “strut element” forsimplicity. Usually, each strut element can be defined by across-sectional profile as having a width and a thickness, and includinga first end and a second end bounding a length. The stent element can besubstantially linear, arced, rounded, squared, combinations thereof, orother configurations. The strut element can include a bumper, crossbar,connector, interconnector, intersection, elbow, foot, ankle, toe, heel,medial segment, lateral segment, coupling, sleeve, combinations thereof,or the like, as described in more detail below. The strut element canhave improved structural integrity by including crack-inhibitingfeatures, which are described in detail in the incorporated references.

Usually, the annular elements can include a plurality ofcircumferentially-adjacent crossbars that are interconnected end-to-endby an elbow connection, intersection, or a foot extension. As such, atleast one annular element or endoprosthesis can include an elbow,intersection, or a foot extension (foot) extending between at least onepair of circumferentially-adjacent crossbars. The elbow or foot can thusdefine an apex between the pair of circumferentially-adjacent crossbarsof the annular element or endoprosthesis. Also, an intersection can havea shape similar to a crossbar or interlinked crossbars so as to providea junction between two coupled pairs of circumferentially-adjacentcrossbars.

The elbow can be configured in any shape that connects adjacent ends ofcircumferentially-adjacent crossbars, and can be described as having aU-shape, V-shape, L-shape, X-shape, Y-shape, H-shape, K-shape, or thelike. The elbow and/or intersection can be configured in any shape thatconnects longitudinal and circumferentially adjacent crossbars, and canbe described as having a cross shape, X-shape, Y-shape, H-shape,K-shape, or the like. The foot can have a foot shape having a first footportion extending circumferentially from an end of one of the adjacentstrut members and a second foot portion extending circumferentially froma corresponding end of the other of the circumferentially-adjacent strutmembers. In combination, the first and second foot portions generallydefine an ankle portion connected to a toe portion through a medialsegment and the toe portion connected to a heel portion through alateral segment.

As described herein, an endoprosthesis, in one configuration, caninclude two or more interconnected annular elements. Each annularelement can generally define a ring-like structure extendingcircumferentially about a longitudinal or central axis. Thecross-sectional profile of each annular element can be at least arcuate,circular, helical, or spiral, although alternative cross-sectionalprofiles, such as oval, oblong, rectilinear or the like, can be used.The different annular elements can be defined as having the samecharacterization or different characterizations.

The first and second annular elements generally define a tubularstructure. For example, each annular element can define a continuousclosed ring such that the longitudinally-aligned annular elements form aclosed tubular structure having a central longitudinal axis.Alternatively, each annular element can define an open ring shape suchthat a rolled sheet, open tubular, or “C-shape” type structure isdefined by the annular elements. That is, the annular element is notrequired to be closed. Furthermore, each annular element can definesubstantially a 360-degree turn of a helical pattern or spiral, suchthat the end of one annular element or endoprosthesis can be joined withthe corresponding end of a longitudinally-adjacent annular element orendoprosthesis to define a continuous helical pattern along the lengthof the endoprosthesis.

FIG. 1 is a side view of a flattened portion of an embodiment of anendoprosthesis 1 a. The illustrated endoprosthesis is a stent, but itwill be understood that the benefits and features of the presentinvention are also applicable to other types of endoprosthesis or othermedical devices known to those skilled in the art.

For purposes of clarity and not limitation, the endoprosthesis 1 a isillustrated in a planar format. As shown, the endoprosthesis 1 a caninclude a plurality of annular elements 10 aligned longitudinallyadjacent to each other along a longitudinal axis 15 extending from afirst end 16 to a second end 18. Although only two interconnectedannular elements need to be provided for the endoprosthesis, it ispossible that an endoprosthesis include one or a plurality of annularelements 10. As depicted in FIG. 1, at least a first annular element 10a and a second annular element 10 b are identified.

Each annular element 10 can include a set of interconnected strutelements, shown as strut crossbars 20, which are disposedcircumferentially about the longitudinal axis 15; the circumferentialdirection is represented by arrow 17. Each crossbar 20 can have a firstend 22 a and a second end 22 b, referenced generally as end 22. Thefirst end 22 a of selected circumferentially-adjacent crossbars 20 a-bcan be interconnected at elbows 30 that are proximate to a firstlongitudinal side 12 of each annular element 10, and the second end 22 bof selected circumferentially-adjacent crossbars 20 b-c can beinterconnected to define elbows 30 that are proximate to a secondlongitudinal side 14 of the annular element.

Each annular element 10 can be expanded to a deployed configuration asshown in FIG. 1 by altering or opening the angle of the elbows 30interconnecting the circumferentially-adjacent crossbars 20, or can becollapsed into a deployable configuration by closing the angle of theelbows 30. Also, circumferentially-adjacent elbows 30 on each side 12,14 of the annular element 10 can be spaced apart by a circumferentialdistance D, such that each annular element 10 is expanded by increasingthe distance D and collapsed by decreasing the distance D. At any givencondition between the delivery configuration and the deployedconfiguration, the distance D can be balanced or constant from one setof circumferentially-adjacent elbows to the next, or it can be varied ifdesired.

Selected elbows 30 on each side 12, 14 of the annular element 10 can bedefined by interconnecting corresponding ends 22 ofcircumferentially-adjacent crossbars 20 a-b directly together to form azigzag pattern of alternating U-shapes, V-shapes, L-shapes, combinationsthereof, or the like when deployed. Alternatively, an elbow 30 can beprovided between the corresponding ends of adjacent crossbars to formanother contoured shape, such as by using a straight elbow member toform a flat connection configuration.

FIG. 1 also depicts an embodiment of a foot extension 40 that can extendbetween a pair 24 of circumferentially-adjacent crossbars 20 d-e of eachannular element 10. As depicted, the foot extension 40 can include anankle 41 that circumferentially couples an end 22 of one of the adjacentcrossbars 20 d to a medial segment 44. The medial segment 44 extendsfrom the ankle 41 to a toe 48 that circumferentially couples the medialsegment to a lateral segment 46. The lateral segment 46 can extend fromthe toe 48 to a heel 42 that circumferentially couples the lateralsegment to the next circumferentially-adjacent crossbar 20 e.Accordingly, the juncture of the crossbar 20 d and the medial segment 44can define a circumferentially-extending toe portion 48 of the footextension 40; the juncture of the medial segment 44 and the lateralsegment 46 defines a circumferentially-extending toe portion 48 of thefoot extension 40; and the juncture of the lateral segment 46 andcrossbar 20 e defines a circumferentially-extending toe portion 48 ofthe foot extension 40. Each portion of the foot extension 40, as well aseach of the circumferentially-adjacent crossbars 20, can have asubstantially uniform cross-sectional profile illustrated by asubstantially uniform width W and thickness (not shown).

For purposes of discussion and not limitation, FIG. 1 shows that a toeportion 48 can extend in a first circumferential direction a distancegreater than the distance the heel portion 42 of the foot extension 40extends in an opposite circumferential direction. As such, the entiretyof the foot extension 40 can extend in the circumferential direction ofthe toe portion 48. Furthermore, at least one of the medial segment 44or lateral segment 46 can open foot region 49.

The adjacent annular elements 10 a-10 b or 10 c-10 d can beinterconnected with an interconnector 50 as described herein. Forexample, the interconnector 50 can have a form of a means for reducingforce transmission between adjacent annular elements. Stated anotherway, the interconnector 50, optionally referred to as a force absorberor force absorbing connector, can include one or more force absorbingmembers that allow limited movement of adjacent annular elements, whilereducing the possibility of cracking and fatigue failure due to themovement of adjacent annular elements. As such, the endoprosthesis 1 acan include a plurality of interconnectors 50 to connect adjacentannular elements 10 a-10 b or 10 c-10 d. Each interconnector 50 caninclude a first bending member or shock 52 and a second bending memberor shock 54, which can bend toward each other to separate the adjacentannular elements 10 a-10 b or 10 c-10 d or bend away from each other tobeing adjacent annular elements closer together. Accordingly, theinterconnector 50 can include a first bending point 60 opposite of asecond bending point 64. The first bending member or shock 52 can haveat least a first arm 66 and a second arm 67. The second bending memberor shock 54 can have at least a first arm 68 and a second arm 69. Theinterconnector 50 can couple with a first crossbar 20 of a first annularelement 10 c at a first coupling 62 a, and couple with a second crossbarof a second annular element 10 d at a second coupling 62 b.

The endoprosthesis 1 a can be easily deployed because of the improvedflexibility provided within each annular element 10 or between adjacentannular elements 10 a-10 b. As such, the resiliently-flexible bendingmembers or shocks 52, 54 can cooperate so as to enable theendoprosthesis 1 a to bend around a tight corner by the bending membersor force-absorbing members on one side of the annular elementcontracting while bending members or force-absorbing members on anopposite side expanding. Also, the combination of elbows 30, footextensions 40, and/or resiliently flexible interconnectors 50 can allowfor radial, longitudinal, torsional, or bending loading to be absorbedwithout cracking, fracturing or damage occurring to the endoprosthesis 1a. Moreover, the resiliently-flexible interconnectors 50 can allowadjacent annular elements to move independently with respect to eachother in radial, longitudinal, and cross directions.

While FIG. 1 illustrates one type of endoprosthesis, the generalteachings thereof can be applied to other types of endoprostheses. Thisincludes other types of stents that have different strut elements indifferent shapes and configurations. As such, FIG. 1 is provided as anexample of one type of endoprosthesis that can be coated with thepolymer/drug of the present invention in order to achieve preferentialdrug delivery into lumen tissue adjacent to the endoprosthesis.

In one embodiment, the present invention can include a drug elutingstent that has a stent body, a polymeric coating, and a lipophilic drug.The polymeric coating can have a lipophilic element and be disposed onthe stent body. The lipophilic drug can have a bioactivity that inhibitscell proliferation, and can be disposed in the polymeric coating.However, any lipophilic drug with any activity can be used for thetreatment of an appropriate condition.

In one embodiment, the present invention can include a drug elutingstent that has a stent body, a polymeric coating, and a hydrophilicdrug. The polymeric coating can have a hydrophilic element and bedisposed on the stent body. For example, the hydrophilic drug can have abioactivity that inhibits cell proliferation, and can be disposed in thepolymeric coating. However, any hydrophilic drug with any activity canbe used for the treatment of an appropriate condition.

In one embodiment, the present invention can include a drug elutingstent that has a stent body, a polymeric coating, and a amphipathic drughaving both hydrophilic and lipophilic components. The polymeric coatingcan have a hydrophilic and/or hydrophilic element and be disposed on thestent body. For example, the amphipathic drug can have a bioactivitythat inhibits cell proliferation, and can be disposed in the polymericcoating. However, any amphipathic drug with any activity can be used forthe treatment of an appropriate condition.

The drug can be present in the polymer at an amount from about 10 ug/cm²(micrograms drug/area of stent) to about 2000 ug/cm², more preferablyfrom about 100 ug/cm² to about 1000 ug/cm², and most preferably fromabout 200 ug/cm² to about 500 ug/cm². In exemplary stents, the drug perarea can include 150 ug/cm² to about 500 ug/cm², more preferably fromabout 175 ug/cm² to about 400 ug/cm², and most preferably from about 200ug/cm² to about 300 ug/cm². Within this narrower range, the drug perarea can include 210 ug/cm² to about 275 ug/cm², more preferably fromabout 215 ug/cm², to about 250 ug/cm², and most preferably 225 ug/cm²±10ug/cm².

In one embodiment, the amount of drug on the stent can be described asthe total amount of drug per stent. Accordingly, the amount of drug perstent can be from about 0.5 mg to about 12 mg, more preferably fromabout 0.75 mg to about 10 mg, and most preferably from about 1 mg toabout 5 mg.

In one embodiment, the amount of drug on the stent can be described asthe total amount of drug for a stent of a specific length. The amount ofdrug per stent can be from about 0.5 mg to about 12 mg for stentsranging from about 10 mm to about 300 mm, and more preferably from about20 mm to about 150 mm stent lengths. This includes about 0.5 mg to about5 mg, more preferably from about 0.75 mg to about 2.5 mg, and mostpreferably about 1 mg for a stent having a length from about 10 mm toabout 30 mm, more preferably from about 15 mm to about 25 mm, and mostpreferably about 20 mm. This also includes about 2 mg to about 6 mg,more preferably about 3 mg to about 5 mg, and most preferably from about3.5 mg to about 4 mg or about 3.8 mg for a stent having a length fromabout 60 mm to about 100 mm, more preferably from about 70 mm to about90 mm, and most preferably about 80 mm. Additionally, this can includeabout 4 mg to about 8 mg, more preferably from about 5 mg to about 7 mg,and most preferably about 6 mg for a stent having a length from about130 mm to about 170 mm, more preferably from about 140 mm to about 160mm, and most preferably about 150 mm.

The polymeric coating and drug are configured to cooperate so as to forma diffusion pathway (e.g., lipophilic, hydrophilic and/or amphipathic)with tissue when the stent is disposed in a body lumen such that thedrug preferentially diffuses into the tissue over a body fluid passingthrough the body lumen such that a maximum systemic blood concentrationof the drug is less than or about 30 ng/ml, more preferably less than orabout 20 ng/ml, and most preferably less than or about 10 ng/ml.

In one embodiment, the polymeric coating can control the systemicdelivery of the drug so as to retain a sufficiently low concentration inorder to inhibit negative systemic side effects. This can include a 100mm stent having about 3.8 mg drug eluting the drug so as to obtain ablood maximum concentration (i.e., Cmax) from about 0.6 ng/ml to about15 ng/ml, more preferably from about 1 ng/ml to about 10 ng/ml, evenmore preferably from about 2 ng/ml to about 5 ng/ml, and most preferablyabout 3 ng/ml. This can also include a 200 mm stent having about 7.5 mgdrug eluting the drug so as to obtain a blood Cmax from about 1.5 ng/mlto about 30 ng/ml, more preferably from about 3 ng/ml to about 15 ng/ml,even more preferably from about 5 ng/ml to about 10 ng/ml, and mostpreferably about 6 ng/ml. Additionally, this can include a 300 mm stenthaving about 12 mg drug eluting the drug so as to obtain a blood Cmaxfrom about 2 ng/ml to about 40 ng/ml, more preferably from about 4 ng/mlto about 30 ng/ml, even more preferably from about 6 ng/ml to about 20ng/ml, and most preferably about 9 ng/ml.

In one embodiment, the systemic delivery of the drug can becharacterized as concentration of drug per length of stent. As such, thesystemic delivery of the drug can provide a blood maximum concentrationthat can be from about 0.6 pg/ml per millimeter (mm) of stent (e.g., 0.6pg drug per ml of blood per mm of stent) to about 15 pg/ml per mm ofstent, more preferably from about 1 pg/ml per mm of stent to about 10pg/ml per mm of stent, even more preferably about 2 pg/ml per mm ofstent to about 5 pg/ml per mm of stent, and most preferably about 3pg/ml per mm of stent.

In one embodiment, the systemic delivery of the drug can becharacterized as concentration of drug per amount of total amount ofdrug on the stent. As such, the systemic delivery of the drug provide ablood maximum concentration can be from about 0.16 ng/ml per milligram(mg) of drug on the stent to about 4 ng/ml per mg total drug, morepreferably from about 0.2 ng/ml per mg total drug to about 3.3 ng/ml permg total drug, even more preferably about 0.5 ng/ml per mg total drug toabout 2.5 ng/ml per mg total drug, and most preferably about 0.75 ng/mlper mg total drug to about 0.8 ng/ml per mg total drug.

In one embodiment, the stent body is comprised of a superelastic alloy,such as nitinol. The nitinol can have an ethylenevinylalcohol copolymercoating disposed thereon. A therapeutically effective amount ofeverolimus can be disposed in the polymeric coating so as to be presentat an amount greater than or equal to about 150 ug/cm². The polymercoating and everolimus are configured so as to cooperate to form alipophilic diffusion pathway with tissue when the stent is disposed in abody lumen such that the everolimus preferentially diffuses into thetissue over a body fluid passing through the body lumen and such that amaximum systemic blood concentration of everolimus is less than about 10ng/ml. In one aspect, the drug can present in an amount greater than orequal to about 200 ug/cm² and the maximum systemic blood concentrationof the drug can be less than about 5 ng/ml. This can also be similar forhydrophilic and amphipathic drugs.

In one embodiment, the drug eluting stent produces a systemic bloodconcentration of the drug that in turn produces at least one of thefollowing: a maximum kidney concentration of less than or about 50 ng/g,more preferably less than or about 40 ng/g, and most preferably lessthan or about 30 ng/g; a maximum lung concentration of less than orabout 45 ng/g, more preferably less than or about 35 ng/g, and mostpreferably less than or about 25 ng/g; a maximum muscle concentration ofless than or about 35 ng/g, less than or about 30 ng/g, and mostpreferably less than or about 25 ng/g; a maximum liver concentration ofless than or about 30 ng/g, more preferably less than or about 25 ng/g,and most preferably less than or about 17 ng/g; or a maximum spleenconcentration of less than or about 35 ng/g, more preferably less thanor about 30 ng/g, and most preferably less than or about 25 ng/g.

In one embodiment, the stent can be characterized by one of thefollowing: the drug is present at greater than or about 1070 ug on thestent body that is about 10×28 mm so as to produce a maximum bloodconcentration of less than or about 3 ng/ml and a maximum lumen tissueconcentration of greater than or about 5000 ng/g; the drug is present atgreater than or about 1070 ug on the stent body that is about 8×28 mm soas to produce a maximum blood concentration of less than or about 3ng/ml and a maximum lumen tissue concentration of greater than or about8000 ng/g; the drug is present at greater than or about 3209 ug on thestent body that is about 8×28 mm so as to produce a maximum bloodconcentration of less than or about 5 ng/ml and a maximum lumen tissueconcentration of greater than or about 20000 ng/g; or the drug ispresent at greater than or about 3777 ug on the stent body that is about7×100 mm so as to produce a maximum blood concentration of less than orabout 10 ng/ml and a maximum lumen tissue concentration of greater thanor about 15000 ng/g.

II. Endoprosthesis Compositions

The drug eluting endoprostheses of the present invention can be made ofa variety of materials, such as, but not limited to, those materialswhich are well known in the art of endoprosthesis (e.g., stent)manufacturing. This can include, but is not limited to, anendoprosthesis body having a primary material. Alternatively, at leasttwo of the annular elements or different portions can be made ofdifferent materials. Generally, the materials for the endoprosthesis canbe selected according to the structural performance and biologicalcharacteristics that are desired.

In one configuration, the endoprosthesis body has multiple layers, withat least one layer being applied to a primary material forming theannular elements. As such, at least one annular element can havemultiple layers that are different from at least one other annularelement. The multiple layers can be resiliently flexible materials orrigid and inflexible materials, and selected combinations thereof. Forexample, materials such as Ti3A12.5V, Ti6Al4V, 3-2.5Ti, 6-4Ti andplatinum may be particularly good choices for adhering to a flexiblematerial, such as, but not limited to, nitinol and providing good crackarresting properties. The use of resiliently flexible materials canprovide force-absorbing characteristics to the structures,interconnectors, and/or other endoprosthesis components, which can alsobe beneficial for absorbing stress and strains, which may inhibit crackformation at high stress zones. Also, the multiple layers can be usefulfor applying radiopaque materials to selected annular elements, such asend annular elements to provide different characteristics. For example,types of materials that are used to make an endoprosthesis can beselected so that the endoprosthesis is capable of being collapsed duringplacement and expanded when deployed. Usually, the endoprosthesis can beself-expanding, balloon-expandable, or can use some other well-knownconfiguration for deployment. For purposes of illustration and notlimitation, reference is made generally to self-expanding embodimentsand balloon-expandable embodiments of the endoprosthesis of the presentinvention; however, other types of endoprostheses can be configured inaccordance with the present invention.

Embodiments of the endoprosthesis body can include a material made fromany of a variety of known suitable materials, such as a shaped memorymaterial (SMM). For example, the SMM can be shaped in a manner thatallows for restriction to induce a substantially tubular, linearorientation while within a delivery shaft, but can automatically retainthe memory shape of the endoprosthesis once extended from the deliveryshaft. SMMs have a shape memory effect in which they can be made toremember a particular shape. Once a shape has been remembered, the SMMmay be bent out of shape or deformed and then returned to its originalshape by unloading from strain or heating. Typically, SMMs can be shapememory alloys (SMA) comprised of metal alloys, or shape memory plastics(SMP) comprised of polymers. The materials can also be referred to asbeing superelastic.

Usually, an SMA can have any non-characteristic initial shape that canthen be configured into a memory shape by heating the SMA and conformingthe SMA into the desired memory shape. After the SMA is cooled, thedesired memory shape can be retained. This allows for the SMA to bebent, straightened, compacted, and placed into various contortions bythe application of requisite forces; however, after the forces arereleased, the SMA can be capable of returning to the memory shape. Themain types of SMAs are as follows: copper-zinc-aluminium;copper-aluminium-nickel; nickel-titanium (NiTi) alloys known as nitinol;nickel-titanium platinum; nickel-titanium palladium; andcobalt-chromium-nickel alloys or cobalt-chromium-nickel-molybdenumalloys known as elgiloy alloys. The temperatures at which the SMAchanges its crystallographic structure are characteristic of the alloy,and can be tuned by varying the elemental ratios or by the conditions ofmanufacture.

For example, the primary material of an endoprosthesis can be of a NiTialloy that forms superelastic nitinol. In the present case, nitinolmaterials can be trained to remember a certain shape, straightened in ashaft, catheter, or other tube, and then released from the catheter ortube to return to its trained shape. Also, additional materials can beadded to the nitinol depending on the desired characteristic. The alloymay be utilized having linear elastic properties or non-linear elasticproperties.

An SMP is a shape-shifting plastic that can be fashioned into anendoprosthesis in accordance with the present invention. Also, it can bebeneficial to include at least one layer of an SMA and at least onelayer of an SMP to form a multilayered body; however, any appropriatecombination of materials can be used to form a multilayeredendoprosthesis. When an SMP encounters a temperature above the lowestmelting point of the individual polymers, the blend makes a transitionto a rubbery state. The elastic modulus can change more than two ordersof magnitude across the transition temperature (Ttr). As such, an SMPcan formed into a desired shape of an endoprosthesis by heating it abovethe Ttr, fixing the SMP into the new shape, and cooling the materialbelow Ttr. The SMP can then be arranged into a temporary shape by force,and then resume the memory shape once the force has been applied.Examples of SMPs include, but are not limited to, biodegradablepolymers, such as oligo(ε-caprolactone)diol, oligo(ρ-dioxanone)diol, andnon-biodegradable polymers such as, polynorborene, polyisoprene, styrenebutadiene, polyurethane-based materials, vinyl acetate-polyester-basedcompounds, and others yet to be determined. As such, any SMP can be usedin accordance with the present invention.

An endoprosthesis body having at least one layer made of an SMM orsuitable superelastic material and other suitable layers can becompressed or restrained in its delivery configuration within a deliverydevice using a sheath or similar restraint, and then deployed to itsdesired configuration at a deployment site by removal of the restraintas is known in the art. An endoprosthesis body made of athermally-sensitive material can be deployed by exposure of theendoprosthesis to a sufficient temperature to facilitate expansion as isknown in the art.

Also, the endoprosthesis body can be comprised of a variety of knownsuitable deformable materials, including stainless steel, silver,platinum, tantalum, palladium, nickel, titanium, nitinol, nitinol havingtertiary materials (U.S. 2005/0038500, which is incorporated herein byspecific reference), niobium-tantalum alloy optionally doped with atertiary material (U.S. 2004/0158309, 2007/0276488, and U.S. Ser. No.12/070,646, which are each incorporated herein by specific reference)cobalt-chromium alloys, or other known biocompatible materials. Suchbiocompatible materials can include a suitable biocompatible polymer inaddition to or in place of a suitable metal. The polymericendoprosthesis can include biodegradable or bioabsorbable materials,which can be either plastically deformable or capable of being set inthe deployed configuration. If plastically deformable, the material canbe selected to allow the endoprosthesis to be expanded in a similarmanner using an expandable member so as to have sufficient radialstrength and scaffolding and also to minimize recoil once expanded. Ifthe polymer is to be set in the deployed configuration, the expandablemember can be provided with a heat source or infusion ports to providethe required catalyst to set or cure the polymer.

In one embodiment, the stent or other medical device is made from asuperelastic alloy such as nickel-titanium or nitinol, and includes aternary element selected from the group of chemical elements consistingof iridium, platinum, gold, rhenium, tungsten, palladium, rhodium,tantalum, silver, ruthenium, or hafnium. The added ternary elementimproves the radiopacity of the nitinol stent comparable to that of astainless steel stent of the same size and strut pattern coated with athin layer of gold. The nitinol stent has improved radiopacity yetretains its superelastic and shape memory behavior and further maintainsa thin strut/wall thickness for high flexibility. For example, the stentaccording to the present invention has 42.8 atomic percent nickel, 49.7atomic percent titanium, and 7.5 atomic percent platinum.

In one embodiment, the implant can be made at least in part of a highstrength, low modulus metal alloy comprising Niobium, Tantalum, and atleast one element selected from the group consisting of Zirconium,Tungsten, and Molybdenum. The medical devices according to the presentinvention provide superior characteristics with regard tobio-compatibility, radio-opacity and MRI compatibility.

Furthermore, the endoprosthesis body can be formed from a ceramicmaterial. In one aspect, the ceramic can be a biocompatible ceramicwhich optionally can be porous. Examples of suitable ceramic materialsinclude hydroxylapatite, mullite, crystalline oxides, non-crystallineoxides, carbides, nitrides, silicides, borides, phosphides, sulfides,tellurides, selenides, aluminum oxide, silicon oxide, titanium oxide,zirconium oxide, alumina-zirconia, silicon carbide, titanium carbide,titanium boride, aluminum nitride, silicon nitride, ferrites, ironsulfide, and the like. Optionally, the ceramic can be provided assinterable particles that are sintered into the shape of anendoprosthesis or layer thereof.

Moreover, the endoprosthesis body can include a radiopaque material toincrease visibility during placement. Optionally, the radiopaquematerial can be a layer or coating any portion of the endoprosthesis.The radiopaque materials can be platinum, tungsten, silver, stainlesssteel, gold, tantalum, bismuth, barium sulfate, or a similar material.

It is further contemplated that the external surface and/or internalsurface of the endoprosthesis body (e.g., exterior and luminal surfaces)as well as the entire body can be coated with another material having acomposition different from the primary endoprosthetic material. The useof a different material to coat the surfaces can be beneficial forimparting additional properties to the endoprosthesis, such as providingradiopaque characteristics, drug-reservoirs, and improvedbiocompatibility.

In one embodiment, at least one biocompatible polymeric layer can be acoating that is applied over the entire endoprosthesis body, or toselect portions. Examples of such biocompatible polymeric materials caninclude a suitable hydrogel, hydrophilic polymer, hydrophobic polymerbiodegradable polymers, bioabsorbable polymers, and monomers thereof.Examples of such polymers can include nylons, poly(alpha-hydroxyesters), polylactic acids, polylactides, poly-L-lactide,poly-DL-lactide, poly-L-lactide-co-DL-lactide, polyglycolic acids,polyglycolide, polylactic-co-glycolic acids, polyglycolide-co-lactide,polyglycolide-co-DL-lactide, polyglycolide-co-L-lactide, polyanhydrides,polyanhydride-co-imides, polyesters, polyorthoesters, polycaprolactones,polyesters, polyanydrides, polyphosphazenes, polyester amides, polyesterurethanes, polycarbonates, polytrimethylene carbonates,polyglycolide-co-trimethylene carbonates, poly(PBA-carbonates),polyfumarates, polypropylene fumarate, poly(p-dioxanone),polyhydroxyalkanoates, polyamino acids, poly-L-tyrosines,poly(beta-hydroxybutyrate), polyhydroxybutyrate-hydroxyvaleric acids,polyethylenes, polypropylenes, polyaliphatics, polyvinylalcohols,polyvinylacetates, hydrophobic/hydrophilic copolymers, alkylvinylalcoholcopolymers, ethylenevinylalcohol copolymers (EVAL),propylenevinylalcohol copolymers, polyvinylpyrrolidone (PVP),combinations thereof, polymers having monomers thereof, or the like.Additionally, the coating can include hydrophilic and/or hydrophobiccompounds, polypeptides, proteins, amino acids, polyethylene glycols,parylene, heparin, phosphorylcholine, or the like.

The coatings can also be provided on the endoprosthesis to facilitatethe loading or delivery of beneficial agents or drugs, such astherapeutic agents, pharmaceuticals and radiation therapies. As such,the endoprosthetic material and/or holes can be filled and/or coatedwith a biodegradable material.

Accordingly, the polymeric coating material can contain a drug orbeneficial agent to improve the use of the endoprosthesis. Such drugs orbeneficial agents can include antithrombotics, anticoagulants,antiplatelet agents, thrombolytics, antiproliferatives,anti-inflammatories, agents that inhibit hyperplasia, inhibitors ofsmooth muscle proliferation, antibiotics, growth factor inhibitors, orcell adhesion inhibitors, as well as antineoplastics, antimitotics,antifibrins, antioxidants, agents that promote endothelial cellrecovery, antiallergic substances, radiopaque agents, viral vectorshaving beneficial genes, genes, siRNA, antisense compounds,oligionucleotides, cell permeation enhancers, and combinations thereof.Another example of a suitable beneficial agent is described in U.S. Pat.No. 6,015,815 and U.S. Pat. No. 6,329,386 entitled “Tetrazole-containingrapamycin analogs with shortened half-lives”, the entireties of whichare herein incorporated by reference.

In addition to various medical devices, the coatings on these devicesmay be used to deliver therapeutic and pharmaceutic agents including:anti-proliferative/antimitotic agents including natural products such asvinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine),paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide),antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin, enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents suchas G(GP) II_(b)/III_(a) inhibitors and vitronectin receptor antagonists;anti-proliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC);anti-proliferative/antimitotic antimetabolites such as folic acidanalogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine,and cytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen);anti-coagulants (heparin, synthetic heparin salts and other inhibitorsof thrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory; antisecretory (breveldin);anti-inflammatory: such as adrenocortical steroids (cortisol, cortisone,fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone,triamcinolone, betamethasone, and dexamethasone), non-steroidal agents(salicylic acid derivatives i.e. aspirin; para-aminophenol derivativesi.e. acetaminophen; indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac,and ketorolac), arylpropionic acids (ibuprofen and derivatives),anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids(piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone),nabumetone, gold compounds (auranofin, aurothioglucose, gold sodiumthiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), everolimus, azathioprine, mycophenolate mofetil);angiogenic agents: vascular endothelial growth factor (VEGF), fibroblastgrowth factor (FGF); angiotensin receptor blockers; nitric oxide donors;antisense oligionucleotides and combinations thereof; cell cycleinhibitors, mTOR inhibitors, and growth factor receptor signaltransduction kinase inhibitors; retenoids; cyclin/CDK inhibitors; HMGco-enzyme reductase inhibitors (statins); and protease inhibitors. Also,it should be recognized that many active agents have multiplepharmaceutical uses other than those specifically recited.

In one configuration, the external surfaces of an endoprosthesis caninclude a coating comprised of polytetrafluorethylene (PTFE), expandedPTFE (ePTFE), Dacron, woven materials, cut filaments, porous membranes,harvested vessels and/or arteries, or others such materials to form astent graft prosthesis. Similarly, a medical device, such as a valve, aflow regulator or monitor device, can be used with the endoprosthesis,such that the endoprosthesis functions as an anchor for the medicaldevice within the body lumen.

In one configuration, different external surfaces of an endoprosthesis,such as a low stress zone less susceptible to flexing, can be coatedwith functional layers of an imaging compound or radiopaque material.The radiopaque material can be applied as a layer at low stress zones ofthe endoprosthesis. Also, the radiopaque material can be encapsulatedwithin a biocompatible or biodegradable polymer and used as a coating.For example, the suitable radiopaque material can be palladium platinum,tungsten, silver, stainless steel, gold, tantalum, bismuth, bariumsulfate, or a similar material. The radiopaque material can be appliedas layers on selected surfaces of the endoprosthesis using any of avariety of well-known techniques, including cladding, bonding, adhesion,fusion, deposition or the like.

III. Superelastic Everolimus Eluting Stent With EthylenevinylalcoholCoating

In one embodiment, the present invention can include a drug elutingstent that is self expanding. The stent can have a structural body thatis prepared from a superelastic material that has shape memory, such asnitinol or the like. The structural body can be coated with at least onepolymeric coating, such as ethylenevinylalcohol copolymer (i.e., EVAL),that functions as a drug delivery system that controls the release ofdrug contained therein. The drug contained within the polymer coatingcan be an anti-restinoic drug (e.g., rapamycin, everolimus, analogsthereof, and the like) or other drug useful for inhibiting cellproliferation within the vascular lumen. The drug can be any drug havinga therapeutic benefit for treating and/or preventing a disease orcondition. The polymer coating that contains the drug can also be coatedby another layer of the same or different polymer that further controlsthe drug release profile from the stent.

In one embodiment, the stent of the present invention is aneverolimus-eluting self-expanding nitinol stent with a elutionrate-controlling polymeric coating prepared from ethylenevinylacetatecopolymers. The stent was designed to address and overcome threepotential shortcomings of prior self-expanding DES, namely (1)inadequate drug delivery to the target tissue, (2) short profiles ofelution leading to transiently high systemic drug concentrations, and(3) a tendency towards strut fracture when implanted into the SFA. Thedesign features of the present invention that address these drawbacksare detailed below.

In one embodiment, a coated stent can be loaded with a relatively highoverall drug content (e.g., 225 μg everolimus/cm² stent area) ascompared to other coronary stents that elute analogs of everolimus(e.g., 140 μg sirolimus/cm² or 160 μg zotarolimus/cm²). Everolimus(40-O-(2-hydroxyethyl)-rapamycin; Novartis Pharmaceuticals Corporation,Basel, Switzerland) is a macrolide immunosuppressant analog of rapamycin(i.e., sirolimus) that, in conjunction with cyclosporine, has been shownto be effective in inhibiting chronic rejection episodes of solid organtransplants. Its oral formulation is marketed outside the United Statesunder the trade name Certican®. Everolimus effectively inhibitsneointimal hyperplasia in animal models and, when formulated ontocoronary stents at a dose of 150 μg everolimus/cm² stent area, itreduces restenosis as compared to bare metal or paclitaxel-elutingstents. The amount of 225 μg everolimus/cm² stent area is an exemplarydose for the drug eluting stent embodiment as this dose roughlyrepresents a 2:1 increase in dose/mm² arterial area as compared to thecoronary DES formulation.

In one embodiment, the drug eluting stent in accordance with the presentinvention, which is referred to herein as “STENT A” is characterized asfollows: a structural body made of nitinol or other similar superelasticalloy; having a maximum diameter when expanded of 3 mm to about 20 mm,more preferably from about 3.5 mm to about 15 mm, and most preferablyfrom about 4 mm to about 12 mm; having a minimum inner diameter when ina deployable of 0 um (i.e., touching) to about 1000 um, more preferablyfrom about 0 um to about 500 um, and most preferably from about 0 um toabout 200 um; and having a polymeric coating of ethylenevinylalcohol ata thickness of about 2 um to about 50 um, more preferably from about 4um to about 25 um, even more preferably from about 5 um to about 20 um,and most preferably from about 13 to about 15 um.

Equally important as the total bulk dose of everolimus contained on thestent is its kinetic release profile. Using an EVAL (i.e., ethylenevinyl alcohol) copolymer system, the everolimus eluting stent embodimentwas designed to release drug over a longer period of time as compared tocoronary stents. In contrast to coronary DES, which release drug over˜30 days, the everolimus eluting stent embodiment can release everolimusmore slowly, and thereby eluting approximately 80% of its drug load overthe first days 90 days. A comparison of drug release rates for STENT 1,STENT 2, STENT 3, and the everolimus eluting stent embodiment (i.e.,stent A) of the present invention is shown in FIG. 2A. The comparativelyprolonged everolimus release rate of the stent A embodiment is intendedto roughly match the kinetics of nitinol stent expansion. For example,oversized self-expanding nitinol stents continue to enlarge to theirnominal diameter and potentially remodel the human arterial wall for atleast six months.

The relatively high drug load and slow release profile of the stent Aembodiment can assure that the vessel walls of treated peripheral targetarteries will contain more everolimus for longer periods of timecompared to coronary arteries treated with coronary DES. This is shownin FIG. 2B, which compares porcine arterial drug content for the STENT Aembodiment, STENT 2, and STENT 3 treated vessels.

A second salient feature of the slow drug release of the STENT Aembodiment is that the potential for systemic everolimus overexposure isminimized. In part, this is because everolimus is released slowly, andthereby the maximum systemic blood concentration of everolimus instented patients was much lower (e.g., 3-4 ng/ml for a 100 mm stenthaving about 3.8 mg drug) one hour post-procedure than the recommendedupper therapeutic limit in transplanted patients (e.g., 8 ng/ml) andconsiderably lower than the C_(max) of patients treated with 5 mgeverolimus per day in safety studies (e.g., 114 ng/ml).

In one embodiment, the present invention utilizes a well-characterizednitinol stent. As a result, there are ample in vitro and clinical datato suggest that the stent is able to withstand the chronic mechanicalforces inherent to the SFA. For example, in a comparative retrospectivestudy of three different peripheral stents, radiographic strut fracturewithin the nitinol stent was observed in only 1.8% of cases after a meanfollow-up of 15±9 months. However, fractures of some nitinol stents wereobserved in 28% and 19% of cases, respectively (mean follow-up of 32±16months and 43±24 months, respectively). Similarly, in a randomized,prospective, single-center study of percutaneous transluminalangioplasty (PTA) alone v. PTA with the nitinol stent embodiment, thenitinol stent fracture was observed in only 2% of patients. Finally, ina multicenter single-arm prospective registry, strut fracture of thenitinol stent embodiment was observed in 2.1% (3/143) stents after oneyear. Taken together, the results of these three studies suggest thatthe nitinol stent is well-suited to the environment of the SFA, and thatchronic implantation is not associated with high rates of fracture. Anitinol stent can be configured to include a polymer having a drug so asto be a drug eluting stent in accordance with the present invention.

In one embodiment, the present invention includes an everolimus-eluting,self-expanding nitinol stent. Such a stent can be used to inhibitrestenosis after endovascular intervention in the SFA by selectivelyeluting everolimus into the vasculature tissue in an amountsignificantly higher than systemic elution into the bloodstream. Asprovided herein, there is ample in vitro, in vivo, experimental, andclinical evidence to suggest that the everolimus-eluting, self-expandingnitinol stent (1) delivers a relatively high concentration of everolimusto the target vascular tissue over a prolonged therapeutic interval, (2)minimizes potential systemic exposure to everolimus through a slowsystemic (e.g., blood) release profile, and (3) can withstand and adaptto the rigorous mechanical environment of the SFA.

In one embodiment, the present invention provides a drug-eluting stenthaving a prolonged elution profile with high local concentration and lowsystemic concentration. The stent can include any stent body that isballoon or self expandable. The stent body includes a first coatinglayer disposed therein, which includes a mixture of polymer and drug.The first coating layer includes a second coating layer of polymerdisposed thereon. The first coating layer can be configured to allow theeverolimus to be controllably released from the stent. The secondcoating layer can, optionally with the first coating layer, control therelease of the drug in a manner that prolongs the release profile.

In one aspect, the polymeric coatings can cooperate so as to controlelution of the drug from the stent. This can include facilitatingelution into the tissue adjacent to the stent and inhibiting elutioninto the bloodstream, thereby inhibiting systemic drug. The controlledelution can be accomplished by the coatings and artery tissuesestablishing a diffusion pathway having a steep concentration gradientwith respect to the drug so as to induce the drug to diffuse through thediffusion pathway. The steep concentration gradient is accomplished bythe coatings having a high concentration of drug and the tissue having alow concentration of drug, which thereby promotes diffusion through thediffusion pathway. Also, the coatings, drug, and tissue can providelipophilic and/or hydrophilic diffusion pathways with the tissue being asink to promote diffusion of the drug into the tissue.

Additionally, the diffusion pathway into the vascular tissue can beenhanced by the stent being placed in a blood vessel that passes blood.Blood, while containing some lipid-based components, is significantlymore aqueous that than lipidic because the blood includes a significantamount of water. As such, a lipophilic drug will preferentially diffusethrough a lipophilic diffusion pathway over an aqueous pathway. Thelipophilic drug preferentially diffusing through the lipophilicdiffusion pathway into the tissue adjacent to the stent over diffusioninto the blood attributes to the vascular tissue adjacent to the stentobtaining a therapeutic concentration of drug and the systemconcentration being significantly below a therapeutic concentration andtoxic concentration. Accordingly, systemic effects of the drug can beinhibited by maintaining an extremely low systemic drug concentration,thereby inhibiting the adverse effects of prolonged systemic drug. Thiscan also be accomplished with hydrophilic and/or amphophilic drugs andpolymer components because tissues inherently have water as a majorcomponent.

In one embodiment, the coating/drug combination is configured to providean extended elution profile that can elute substantially constant levelsof drug over 3 months, more preferably over 6 months, and mostpreferably over 9 months. The slow elution kinetics attribute to thesignificantly inhibited systemic elution of the drug and helps tomaintain the systemic of the drug below any therapeutic and/or toxicindex. Additionally, the slow elution kinetics attributes to the drugpreferentially diffusing through the lipophilic diffusion pathwaybecause slow elution kinetics further drive the lipophilic drug througha lipophilic diffusion pathway over diffusing into the blood. Also, theslow elution kinetics can enable the tissue to retain sink-likeproperties with respect to the drug so as to provide a continuouslysteep concentration gradient through the lipophilic diffusion pathway.

In embodiments of the present invention that include self-expandingstents, the stent continually applies pressure to the vascular tissue.This continual application of pressure can cause the tissue to formtroughs that receive the stent elements therein so that the contact areabetween the tissue and the stent is increased. Also, it is possible thatsuch continuous pressure actually facilitates preferential diffusion ofthe drug through the lipophilic diffusion pathway. This can occur by thepressure shortening the diffusion pathway between the stent and thetissue by compression of the lipid membranes and/or compression of thecoating layers.

It is thought, without being bound thereto, that the coating/drugcombination that provides preferential diffusion of the drug through thelipophilic diffusion pathway over diffusion into the systemic bloodsupply cooperates with natural physiological processes in order tofurther differentiate the amount of drug in the vascular tissue adjacentto the sent compared to systemic drug. The difference in drug diffusionpathways that result in extremely low systemic concentrations issupplemented by the physiological functions of drug metabolism. Drugmetabolism occurs mainly in organs that are removed from the vasculartissue, and preferentially not in the vascular tissue. Thisphysiological process naturally further reduces the systemicconcentration of drug without reducing the concentration of drug in thevascular tissue.

In one embodiment, the polymer/drug combination that is configured forprolonged elution can also allow for a substantially greater amount ofdrug loading on the stent. Previously, drug elution profiles have onlyallowed for low quantities of drug to be applied to the stent so as toprevent excessively high elution rates and thereby excessively highlocal and systemic drug concentrations. Some of the previously usedstents with low drug loading concentrations have caused higher systemicdrug concentrations. Now, the polymer/drug combination of the presentinvention can allow for substantially increased drug loading on thestent with reduced systemic concentrations. For example, stents thatproduce excessive systemic concentrations of drug have had relativelylower amounts of drug, such as the following: stent 2 having 140 ug/cm²;stent 3 having 100 ug/cm²; and stent 1 having 90 ug/cm². However, thepolymer/drug combination of the present invention can allow for thestents to have a substantially higher amount of drug loading with lowersystemic blood concentrations. For example, the present invention canhave a drug loading preferably greater than or equal to about 150ug/cm², more preferably greater than or equal to about 200 ug/cm², andmost preferably greater than or equal to about 225 ug/cm².

Similarly, the stents of the present invention can have substantiallymore total drug per stent than the stents that produce excessivesystemic drug concentrations. For example, stents that produce excessivesystemic concentrations of drug have had relatively lower amounts oftotal drug. However, the polymer/drug combination of the presentinvention can allow for the stents to have a substantially higher amountof total drug loading. For example, the present invention can have atotal drug loading preferably greater than or equal to about 1-3 mgtotal drug for a short stent, more preferably greater than or equal toabout 3-6 mg total drug for a medium length stent, and most preferablygreater than or equal to about 6-12 ug total drug for a long stent.

Additionally, the stents of the present invention can have substantiallymore drug per area of artery into which the drug is to diffuse comparedto prior stents. For example, stents that produce excessive systemicconcentrations of drug have had relatively lower amounts of drug perarea of artery, such as the following: stent 2 having 0.86 to 1.3ug/mm²; stent 3 having 0.49 to 63 ug/mm²; and stent 1 having about 0.57to 0.66 ug/mm². However, the polymer/drug combination of the presentinvention can allow for the stents to have a substantially higher amountof drug per area of artery. For example, the present invention can havea drug loading preferably greater than or equal to about 1.25 ug/mm² ofartery, more preferably greater than or equal to about 1.5 ug/mm² ofartery, and most preferably greater than or equal to about 2.0 ug/mm² ofartery.

In one embodiment, the polymeric coating can have a thickness of about 2um to about 50 um, more preferably from about 4 um to about 25 um, evenmore preferably from about 5 um to about 20 um, and most preferably fromabout 13 um to about 15 um. The coating can be uniform or divided intodiscrete layers.

In one embodiment, the polymeric coating can having a primer coatingagainst the metal, a drug-loaded coating disposed on the primer coating,and a topcoat disposed on the drug-loaded coating. This can include theprimer coating being from about 1% to about 20% of the total coatingthickness, more preferably from about 3% to about 15% of the totalcoating thickness, even more preferably from about 5% to about 10% ofthe total coating thickness, and most preferably about 7% of the totalcoating thickness. This can also include the drug-loaded coating beingfrom about 25% to about 90% of the total coating thickness, morepreferably from about 40% to about 80% of the total coating thickness,even more preferably about 50% to about 70% of the total coatingthickness, and most preferably about 60% of the total coating thickness.Additionally, this includes the topcoat being from about 5% to about 50%of the total coating thickness, more preferably from about 15% to about40% of the total coating thickness, more preferably from about 25% toabout 35% of the total coating thickness, and most preferably about 30%of the total coating thickness.

In one example, a 28 mm stent is coated with 234 ug of primer coating,3160 ug of drug-loaded coating, and 600 ug of topcoat. The ratio ofprimer/drug/topcoat layers can be about 1/14/3.

In one embodiment, the prevent invention includes a nitinol stent havinga first ethylenevinylalcohol-everolimus coating on the nitinol body anda second etheylenevinyl alcohol coating thereon. In one aspect, theeverolimus can be included at 1070 ug for a 10×28 mm stent so as toproduce a blood Cmax of less than or about 0.72 ng/ml with a Tmax of 7days, a tissue Cmax of about greater than or about 6607 ng/g with aT_(max) of 3 days, and a half life (t_(1/2)) of about 16.3 days. Inanother aspect, the everolimus can be included at 1070 ug for a 8×28 mmstent so as to produce a blood Cmax of less than or about 2.29 ng/mlwith a Tmax of 1 day, a tissue Cmax of greater than or about 12946 ng/gwith a Tmax of 3 days, and a half life of 11.70 days. In another aspect,the everolimus can be included at 1070 ug for a 8×28 mm stent so as toproduce a blood Cmax of less than or about 2.70 ng/ml with a Tmax of 3days, a tissue Cmax of greater than or about 8709 ng/g with a Tmax of 3days, and a half life of 11.51 days. In another aspect, the everolimuscan be included at 3209 ug for a 8×28 mm stent so as to produce a bloodCmax of less than or about 3.35 ng/ml with a Tmax of 3 days, a tissueCmax of greater than or about 22027 ng/g with a Tmax of 3 days, and ahalf life of 21.26 days. In another aspect, the everolimus can beincluded at 3777 ug for a 7×100 mm stent so as to produce a blood Cmaxof less than or about 9.6 ng/ml with a Tmax of 0.042 days, a tissue Cmaxof greater than or about 16347 ng/g with a Tmax of 3 days, and a halflife of 19.8 days, and which produces a kidney Cmax of less than orabout 25.6 ng/g, a lung Cmax of less than or about 22.8 ng/g, a muscleCmax of less than or about 13.5 ng/g, a liver Cmax of less than or about15.1 ng/g, and a spleen Cmax of less than or about 23.1 ng/g.

IV. Method of Making Endoprostheses

Various different manufacturing techniques are well known and may beused for fabrication of the drug eluting endoprosthesis of the presentinvention. Such manufacturing techniques can be employed to make thedifferent annular elements of the drug eluting endoprosthesis. Forexample, the different annular elements or entire endoprosthesis can beformed from a hollow tube using a known technique, such as lasercutting, EDM, milling, chemical etching, hydro-cutting, and the like.Also, the different annular elements or endoprosthesis can be preparedto include multiple layers or coatings deposited through a claddingprocess such as vapor deposition, electroplating, spraying, or similarprocesses. Also, various other processes can be used such as thosedescribed below and or others known to those skilled in the art in lightof the teaching contained herein.

Optionally, the different annular elements or endoprosthesis can befabricated from a sheet of suitable material, where the sheet is rolledor bent about a longitudinal axis into the desired tubular shape.Additionally, either before or after being rolled into a tube, thematerial can be shaped to include endoprosthetic elements by beingshaped with well-known techniques such as laser-cutting, milling,etching or the like. If desired, the lateral edges of the structure canbe joined together, such as by welding or bonding, to form a closedtubular structure, or the lateral edges can remain unattached to form acoiled, rolled sheet or open tubular structure. Such fabricationtechniques are described in more detail below and known to those skilledin the art.

A. Sintering

A method of making different annular elements or endoprosthesis inaccordance with the present invention can include sintering sinterableparticles to provide a sintered article having the shape of theendoprosthesis. The sintering can be conducted in molds that are in theshape of an endoprosthesis.

In one configuration, the sintered body can be obtained from a moldedgreen body prepared by molding a mixture of sinterable particles with orwithout a binder into the shape of different annular elements orendoprosthesis or body intermediate. Sintering a molded green body thathas the shape of different annular elements or endoprosthesis canprovide a sintered body that can function as an endoprosthesis with noor minimal further processing. Alternatively, after the green body hasbeen formed in the mold and sintered into a hardened endoprosthesis, theprocess can include shaping the sintered body with a stream of energyand/or matter in order to obtain a desired shape. Thus, sintering agreen body in a mold can result in an endoprosthesis that is eitherready for use, or requires additional processing or finishing.

Additionally, the sintered body can be shaped into an endoprosthesis asdescribed herein. Also, the endoprosthesis can be further processedafter sintering and/or shaping such as by grinding, sanding, or the liketo provide enhanced surface characteristics.

B. Drawing Concentric Tubes

In one configuration, multilayered annular elements or endoprosthesis inaccordance with the present invention can be prepared by a drawingprocess that draws two or more distinct concentric tubes into a singletube having two or more layers. Additionally, such a drawing process cancombine multiple concentric tubes into a single multilayered tube. Thedrawing process can be configured to produce junctions separatingadjacent layers or bonds that bond adjacent layers. As such, thesequentially-adjacent concentric tubes can be drawn together andprogressively reduced in a cross-sectional profile until the desiredsize and residual clamping stress is attained.

Accordingly, a metallurgical bond can be prepared with elements of eachsequentially-concentric tube diffusing together and bonding so as toform a strong metallurgical bond. Such a metallurgical bond can beachieved by applying significant pressure and heat to the tubes. Assuch, a metallurgical bond can form a diffusion layer at the interfacebetween sequentially-adjacent concentric tubes (i.e., layers). Thecharacteristics of these diffusion layers can be controlled by theproper heat treatment cycle. In part, this is because the heattreatment, temperature, and time of processing can control the rates oftransfer of the diffusing elements that produce the diffusion layers.Also, the pressure at the interface between layers can be developed soas to result in the residual radial clamping stress in the tube afterdrawing. A similar process can be used in order to couple the adjacentdifferent annular elements or endoprostheses together to form the hybridsegmented endoprosthesis.

In one example of this process, an outer tube of nitinol, a middle tubeof tantalum, and an inner tube of nitinol can be arranged to form thecomposite structure. The multilayered material can be produced to resultin bonding between the layers so as to achieve a residual clampingstress of at least about 50 p.s.i. Accordingly, the annealing processcan be performed within a limited range of time and temperatures. Forexample, the lower limit can be at least about 1550° F. for at least sixminutes, and the upper limit can be less than about 1850° F. for lessthan 15 minutes. A similar process can be used in order to couple theadjacent different annular elements together to form the endoprosthesis.

In another configuration, a metallic interleaf layer can be placedbetween separate tubes so as to bond the tubes together and form amultilayered material. The multiple tubes separated by the metallicinterleaf layer can be drawn together and progressively reduced untilthe desired cross-sectional profile and residual clamping stress isattained, as described above. The drawn tubes can be heat-treated toform a diffusion bond between the separate layers. As such, the metallicinterleaf layer can enhance the diffusion rate or type of diffusingatoms that are transported across a diffusion region between one layerand the interleaf layer. A similar process can be used in order tocouple the adjacent different annular elements together to form theendoprosthesis.

In one configuration, a multilayered sheet can be prepared to haveseparate layers of different materials or the same material. Forexample, the multilayered sheet can have a top layer of nitinol, amiddle layer of tantalum, and a bottom layer of nitinol. The sheet canbe prepared by metallurgically bonding the layers prior to a deepdrawing process, which is well known in the art. During the deep drawingprocess, the sheet can be placed over a die and forced into the die,such as by a punch or the like. A tube having a closed end and a definedwall thickness can be formed in the die. This process can be repeatedusing a series of dies that have progressively decreasing diametersuntil a multilayered tube is formed having the desired diameter and wallthickness. For certain material combinations, intermediate heattreatments can be performed between the progressive drawing operationsto form a multilayered material that is resistant to delaminating. Oncea multilayered tube of desired thickness and dimensions has been formed,the closed end and the curved edges can be cut off. Then, the tube canbe heat treated, as described above, until proper inter-metallic bondsare formed between the layers.

C. Shaping

Accordingly, an endoprosthetic material can be shaped by various methodsas described in more detail below. Such shaping techniques can utilizestreams of energy and/or streams of matter in order to impart shapesinto the endoprosthetic material. The streams of energy include photons,electromagnetic radiation, atomic, and sub-atomic materials, asdescribed above. On the other hand, the streams of matter are consideredto include materials larger than atomic scale particles, and can bemicroscopic or macroscopic in size. In any event, the shaping can bedesigned to direct a stream of energy or a stream of matter at theendoprosthetic material to form an endoprosthetic element and/or holestherein.

In one configuration, a stream of energy can cut, shape, and/or form atube into an endoprostheses by generating heat at the site where thestream intersects the material, as is well known in the art. The thermalinteraction can elevate the local temperature to a point, which can cut,melt, shape, and/or vaporize portions of the endoprosthetic materialfrom the rest of the material.

Accordingly, one configuration of the stream-cutting apparatus canoperate and shape the endoprosthetic material by thermal interactions.As such, any of the thermal processes described herein can be used forthermal-cutting. For example, such thermal interactions can arise fromlaser beam treatment, laser beam machining, electron beam machining,electrical discharge machining, ion beam machining, and plasma beammachining.

In one configuration, by knowing the thermal properties of theendoprosthetic material, precise energy requirements can be calculatedso that the thermal beam provides the appropriate or minimum energy formelting and/or vaporizing the material without significantly meltingundesirable portions of the material. For example, laser beams are acommon form of a stream of energy that can be used to shape theendoprosthetic material. Additionally, there are instances where a laseris preferred over all other cutting techniques because of the nature ofthe resulting endoprosthesis as well as the characteristics of theendoprosthetic material.

In one configuration, an endoprosthesis may be manufactured as describedherein using a femtosecond laser. A femtosecond laser may be desirablein producing an endoprosthesis in accordance with the multilayeredcomposite structure of the present invention because it produces asmaller heat influence zone HIZ or heat affected zone HAZ compared toother lasers, or it can substantially eliminate the HIZ or HAZ. Incomparison, cutting an endoprosthesis using known methods can result inthe tubular material being melted away, and thereby forming the patternin the tubular member. Such melting can result in embrittlement of somematerials due to oxygen uptake into the HIZ.

In one configuration, electrical discharge machining is used to shapeendoprosthetic material and/or form holes in the endoprosthetic materialas desired. As such, electrical discharge machining can be capable ofcutting all types of conductive materials such as exotic metal includingtitanium, hastaloy, kovar, inconel, hard tool steels, carbides, and thelike. In electrical discharge, the main interaction between the streamof energy and the endoprosthetic material is thermal, where heat isgenerated by producing electrical discharges. This can lead to theendoprosthetic material being removed by melting and evaporation. Someexamples of electrical discharge machining include wire electrondischarge machining, CNC-controlled electrical discharge machining,sinker electrical discharge machining, small hole discharge machining,and the like.

In another configuration, a charged particle beam can be used forshaping the endoprosthetic material, wherein electron beams and ionbeams exemplify charged particle beams. A charged particle beam is agroup of electrically-charged particles that have approximately the samekinetic energy and move in approximately the same direction. Usually,the kinetic energies are much higher than the thermal energies ofsimilar particles at ordinary temperatures. The high kinetic energy andthe directionality of these charged beams can be useful for cutting andshaping of the green bodies, as described herein. Additionally, thereare some instances where electron beams or ion beams are preferred overother cutting techniques.

In one configuration, a stream of chemical matter can be used in orderto shape or form holes in the endoprosthetic material. Chemical-jetmilling, for example, provides selective and controlled material removalby jet and chemical action. As such, the process is similar to water-jetcutting, which is described in more detail below. In any event,chemical-jet milling can be useful for shaping various types ofendoprosthetic materials, which provides intricate shaping capabilities.

In another configuration, electrochemical shaping can be based on acontrolled electrochemical dissolution process similar to chemical-jetmilling an endoprosthetic material. As such, the endoprosthetic materialcan be attached to an electrical source in order to allow an electricalcurrent to assist in the shaping.

In one configuration, hydro-cutting or water-jet cutting can be used toshape an endoprosthetic material. Hydro-cutting is essentially awater-jet technology that uses the high force and high pressure of astream of water directed at the endoprosthetic material in order to cutand shape the material as desired. Hydro-cutting can be preferred oversome of the other stream-cutting technologies because it can be free ofheat, flame, and chemical reactions, and can provide a precise coldshaping technique. Also, heated water with or without being doped withreactive chemicals can also be used. Hydro-cutting is particularlysuitable for polymeric endoprostheses, but can be used for metalmaterials when combined with abrasive particles, as described below.

Additionally, hydro-cutting can be enhanced by the introduction ofparticulate materials into the water feed line. As such, somehydro-cutting techniques utilize garnet or other rigid and strongmaterials in order to apply an abrasive cutting force along with theforce applied by the water itself. Also, the hydro-cutting process inthe present invention can be used with or without inclusion of suchabrasives.

Additionally, one of the benefits of hydro-cutting is the ability toreutilize and recycle the spent water-jet material. As such, theendoprosthetic material can be easily separated from the spent water,thereby enabling the recycling and reuse of the water during thehydro-cutting process.

In one configuration, sandblasting, which fits into the regime of streamof matter cutting, can be used to shape an endoprosthetic material byprojecting a high energy stream of sand particles at the material.Sandblasting cuts materials in a manner similar to hydro-cutting,especially when the water-jet is doped with abrasive particulates.Additionally, various other particulate streams other than sand can beused in the stream-cutting techniques and machinery.

D. Additional Processing

An additional step of passivation can be performed during themanufacturing stage of the endoprosthesis in order to form a homogeneousoxide layer for corrosion-resistance. The passivation process may beperformed prior to installation of the markers in accordance with thepresent invention or it may be performed after installation of theradiopaque markers. It can also be done before or after the differentannular elements or endoprostheses are coupled together. Alternatively,multiple passivation processes may be performed, once prior toapplication of the markers, and again after insertion of the markers.

As originally shaped and/or fabricated, the annular elements orendoprosthesis can correspond to a delivery configuration, to a deployedconfiguration, or to a configuration therebetween. The annular elementsor endoprosthesis can be fabricated with a configuration at leastslightly larger than the delivery configuration. In this manner, theendoprosthesis can be crimped or otherwise compressed into its deliveryconfiguration in a corresponding delivery device.

In another configuration, the annular elements or endoprosthesis can beoriginally fabricated from a tube having a diameter corresponding to thedeployed configuration. In this manner, the longitudinally-free portionsof the annular elements (e.g., elbow or foot not at a connectionlocation) and circumferentially-free portions (e.g., the toe and/or heelportion of the foot extensions) can be maintained within the generalcylindrical shape (e.g., diameter) of the endoprosthesis when deployed,so as to avoid such portions from extending radially inward when in thedeployed configuration. The endoprosthesis can be designed to match thetarget vessel in which the endoprosthesis is to be deployed. Forexample, a stent can be provided with an outer diameter in the deployedconfiguration ranging from about 1 mm for neurological vessels to about25 mm for the aorta. Similarly, a stent can be provided with a lengthranging from about 5 mm to about 200 mm. Variations of these dimensionswill be understood in the art based upon the intended application orindication for the endoprosthesis.

Also, the geometry of each component of the endoprosthesis orendoprosthetic element, such as the width, thickness, length and shapeof the strut elements, interconnectors, crossbars, connectors, elbows,foot portions, ankle portions, toe portions, heel portions and the likecan be selected to obtain predetermined expansion, flexibility,foreshortening, coverage scaffolding, and cross-sectional profilecharacteristics. For example, longer crossbars and/or connectors canpromote greater radial expansion or scaffolding coverage. The phasedifference or circumferential alignment between adjacent annularelements likewise can be altered to control coverage and flexibility.Similarly, the number and placement of connection locations and, ifpresent, the connectors, between longitudinally-adjacent annularelements can be selected to obtained the desired flexibility of theendoprosthesis. The number of elbows and/or foot extensions betweenconnection locations also can be varied to achieve desired performancecharacteristics.

E. Coatings

After the endoprosthesis body is formed, a polymeric coating can beapplied thereto. The coating can be applied as is well known in the artof drug eluting stents were polymers are used to retain the drug andallow for diffusion therefrom. Some of the methods for coatingendoprostheses (e.g., stents) with polymers includes dipping, spraying,inkjetting, painting, brushing, rolling, or otherwise depositing thepolymeric coating on the endoprosthesis body. This can include suchprocesses for one or more concentric layers of polymeric coatingmaterials.

In one embodiment, the drug is mixed into a polymeric solution that isapplied to the endoprosthesis by an acceptable method of application.Alternatively, a first layer of polymer can be applied to the stent andthen a drug layer can be applied thereto with a topcoat of polymer beingapplied over the drug layer. In another alternative. A coated stent canbe dipped into a drug solution so that the drug diffuses into thepolymeric coating to achieve the desired amount of drug. In yet anotheralternative, a bare endoprosthesis can have a layer of drug appliedthereto with at least one layer of polymer applied thereto.

After application of a fluid or gelatinous coating, the endoprosthesiscan be dried so that the coating can be substantially solidified. Suchdrying can accomplished by passive or active drying. Passive dryingincludes retaining the coated stent in normal or ambient conditions sothat a natural drying process occurs. Active drying includes the use ofhead or forced air to cause the solvent in the liquid coating toevaporate from the coating, and thereby harden the coating so as to besubstantially solid.

In one embodiment, the coating or plurality of coatings are applied by aplurality of spray layers. For example, the primer coating can be formedfrom about 2-3 passes of spraying polymer, the drug-loaded coating canbe formed from about 26 passes of spraying polymer, and the topcoat canbe formed from about 13 passes of spraying polymer.

V. Method of delivering Hybrid Segmented Endoprosthesis

Generally, the drug eluting endoprosthesis of the present invention canbe delivered into a body of a subject by any method known or developed.For example, the method of using catheters to deploy self-expandable orballoon-expandable stents can be employed.

In one embodiment, the endoprostheses of the present invention areconfigured for use in a body lumen. As such, the present inventionincludes a method of delivering the endoprosthesis into a body lumen ofa subject. Such a method includes: providing an endoprosthesis asdescribed herein; orienting the endoprosthesis into a deliveryorientation with a cross section that is smaller than the body lumen;inserting the endoprosthesis in the delivery orientation into a deliverydevice, such as a deliver catheter that can be configured substantiallyas a catheter for delivering a stent; delivering the endoprosthesis to adesired deployment site within the body lumen of the subject; removingthe endoprosthesis from the delivery device; and expanding theendoprosthesis so as to have an enlarged dimension that applies radialforces to an inner wall of the body lumen.

FIGS. 5A-5B are side views illustrating an embodiment of a drugendoprosthesis and methods of deploying such an endoprosthesis into abody lumen in accordance with the present invention. The endoprosthesis120 a is a drug eluting stent, which is depicted in FIG. 5C to show 3different layers as follows: a stent body layer 124, a polymer/drugcoating 122, and a polymeric topcoat 126 that controls drug diffusionfrom the stent, where 122 a, 124 a, and 126 a designate the deliveryconfiguration and 122 b, 124 b, and 126 b designate the deployedconfiguration.

FIG. 5A is a schematic representation illustrating a delivery system 100for delivering a drug eluting endoprosthesis 120 a into a body lumen140, such as a blood vessel like the vena cava. The delivery systemincludes an endoprosthesis delivery catheter 102 configured fordelivering a drug eluting endoprosthesis 120 a that is retained by thecatheter 102 in a delivery orientation (e.g., radially compressed). Thedelivery catheter 102 includes a delivery member 104 that defines adelivery lumen 107 that is shaped and dimensioned to retain theendoprosthesis 120 a in the delivery orientation. Accordingly, thedelivery member 104 is substantially tubular and configured similarly asany delivery catheter member. An internal surface 106 defined by thedelivery member 104 holds the endoprosthesis 120 a within the deliverycatheter 102.

The delivery system 100 delivers the endoprosthesis 120 a with acatheter 102 similarly to the method of delivering other endoprosthesesinto a body lumen. As such, an insertion site (not shown) is formedthrough the skin (not shown) that traverses into a body lumen 140. Aguidewire (not shown) is then inserted through the insertion site,through the body lumen 140, to the delivery site 144. A catheter (notshown) is then inserted into the body lumen 140 to the delivery site 144over the guidewire, and the guidewire is optionally extracted. Thedelivery catheter 102 is then inserted through the catheter (not shown)until reaching the delivery site 144 and the catheter is withdrawn.

Optionally, the catheter is the delivery catheter 102, and in thisinstance, the delivery catheter 102 is retained at the delivery site 144and the endoprosthesis 120 a is delivered to the delivery site 144through the lumen 107 of the delivery catheter 102. An optional pusheror stop 110, having a lumen (not shown) to receive the guidewire (notshown), can be used to push the endoprosthesis 120 a within the lumen107 of the delivery catheter 102 to the delivery site 144 or limitproximal movement of the endoprosthesis 120 a as the delivery catheter102 is moved proximally to deploy the endoprosthesis 120 a.

Accordingly, the delivery system 100 is inserted through percutaneousinsertion site (not shown) that traverses from the skin (not shown) intothe body lumen 140 until reaching the delivery site 144. The pusher 110includes a distal end 112 that pushes the endoprosthesis 120 a from thedistal end 108 of the delivery member 104. Alternatively, theendoprosthesis 120 a can be disposed at the distal end 108 of thedelivery member 104, and the pusher 110 holds the endoprosthesis 120 aat the delivery site 144 and the delivery member 104 is retracted overthe endoprosthesis 120 a and pusher 110. Thus, the pusher 110 can pushthe endoprosthesis 120 a from the delivery catheter 102 or the deliverymember 104 can be withdrawn over the endoprosthesis 120 a and pusher 110in order to deploy the endoprosthesis 120 a. Combinations of these arealso possible.

FIG. 5B illustrates the endoprosthesis 120 b in the deployedconfiguration at the delivery site 144 within the body lumen 140. Assuch, the endoprosthesis 120 b is radially expanded so as to contact theinner wall 142 of the body lumen 140.

In one embodiment, the present invention can include a method ofextracting the endoprosthesis from the body lumen, which can include:inserting an endoprosthesis-extracting medical device into the bodylumen so as to come into contact with the endoprosthesis; engaging theendoprosthesis-extracting medical device with the endoprosthesis;radially compressing the endoprosthesis so as to have a reduceddimension with a cross section that is smaller than the body lumen; andretrieving the endoprosthesis from the desired deployment site withinthe body lumen of the subject. Optionally, the endoprosthesis can bereceived into the endoprosthesis-extracting medical device, which can besubstantially similar to a catheter.

In one embodiment, at least one of delivering or retrieving theendoprosthesis is performed with a catheter. Catheters configured fordelivering and/or retrieving endoprostheses from a body lumen can beadapted for delivering and/or retrieving the endoprosthesis of thepresent invention.

VI. Lumen Filter

In one embodiment, the medical device of the present invention havingthe drug-loaded polymer coating can be a lumen filter, such as a venacava filter. The drug-loaded polymer coating can provide substantiallythe same drug elution profile with increased local tissue concentrationand decreased blood and systemic concentration as described herein.

In one embodiment, the lumen filter is configured for a use other thanfiltering clots from the lumen; however, such a function can also beperformed. The lumen filter embodiment is configured to deliver the drugloaded in the polymer to the lumen in which the filter is disposedwithout a substantial amount of systemic delivery. As such, the deliveryprofile from the lumen filter can be substantially as shown herein.

As shown in FIGS. 6A-6C, the lumen filter 200 can include asubstantially tubular or conical-shaped body 210, the walls of which canbe partitioned by a slot pattern, web, latticework or the like renderingthe body radially expandable. Additionally, a plurality of tines can beincluded in the body 210 in substantially uniform circumferentialspacing about the proximal end of said tubular body. In a filterintended for femoral vein introduction into the vena cava the tines canbe elongated appendages having hooked terminal ends. In a filterintended for jugular vein introduction the tines can be short spikes.The filter can be delivered to the inferior vena cava by catheters as iswell known in the art, including through the technique and structuresdiscussed above with respect to endoprosthesis 120 a.

The filter can be delivered substantially as described in for theendoprosthesis 120 a in FIGS. 5A-5B, and the elements thereof areinclude in FIGS. 6B-6C. For example, after the proper location isobtained within the body lumen, i.e., the delivery site 144 of FIG. 6Bis attained, the filter 200 can be deployed from the distal end of thecatheter 102 through distal movement of the pusher 110, proximalmovement of catheter 102, or a combination of distal and proximalmovements. With the filter 200 being self-expanding, releasing thefilter 200 from the distal end of the delivery catheter 102 allows thefilter 200 to expand into the body lumen affix the expanded filter 200within the vena cava. After deployment of the expanded filter 200 withinthe vena cava the catheter 102 is withdrawn as shown in FIG. 6C, and thefilter elutes drug as described herein.

In one embodiment, the medical device of the present invention, such asthe drug-coated stent or lumen filter, can be utilized to locallydeliver the drug as described herein. As such, the medical device can beused as a drug delivery system instead of or in concurrence to being astent or a lumen filter.

In one embodiment, the medical device of the present invention, such asthe drug-coated stent or lumen filter, can be configured to systemicallyelute the drug in an amount sufficient for maintaining a therapeuticallyeffective amount of drug in the blood. For example, everolimus,zotarolimus, or other rapamycin analogs can be included in the polymericcoating of the medical device in an amount that systemically deliversthe drug into the blood stream for systemic administration. The amountof drug elution can be configured to be sufficient for providing thetherapeutic benefit of the drug for the treatment and/or prophylaxis inwhich the drug is being used. Such amounts are readily obtainable andthe blood concentration can be achieved by altering (e.g., increasing ordecreasing) the total amount of drug in the polymer.

In one embodiment, the medical device, such as the lumen filter, can beconfigured for substantially systemic drug delivery in addition toand/or instead of local delivery into the adjacent tissue. In such aconfiguration, the medical device is configured to preferentially elutethe drug into the blood over the tissue. This can be accomplished by anyof the following: applying the drug-loaded polymer to at least onefluid-contacting surface of the medical device; coating thetissue-contacting surfaces of the medical device with a coating thatinhibits drug diffusion; and combinations thereof.

In one embodiment, the medical device, which can be in the form of astent, lumen filter, implant, or the like, can be configured as a drugdelivery system that can be a substitute for an oral medication regimen.This can be achieved by the medical device in a suitable form forimplantation into a body cavity, lumen, organ, subcutaneous, or anyother body part. Many medical devices are configured specifically forplacement in the body and any of these medical devices can be configuredfor controlling drug elution so as to obtain a desired systemicconcentration via the configurations described herein. That is, thedrug-loaded polymer that has a long term elution profile can beselectively applied to the medical device. As such, the medical devicebecomes a systemic drug release device instead of a device to treat anarea of stenosis. The drug release device could replace daily pills forindividuals in need of the therapy provided by the drug, such astransplant patients. However, any drug for any condition can be appliedto the medical device in the polymer system described herein fortreatment of any disease.

EXAMPLES Example 1

Stent in vivo experimental pharmacokinetics of the peripheraleverolimus-eluting self-expanding nitinol stent (i.e., STENT A) wereassessed in the porcine model. Briefly, stents were implanted in theiliofemoral arteries, explanted at pre-determined endpoints, and assayedfor drug content by HPLC. The results (e.g., FIG. 2A) showed that thedrug was slowly released from the device over approximately threemonths, at a rate largely independent of stent configuration. Thethree-month release rates considerably prolonged as compared topreviously developed peripheral drug-eluting stents which elute overabout one week (STENT #1) or coronary drug-eluting stents which eluteover about one month (STENT #1 and STENT #2).

Example 2

Tissue in vivo experimental pharmacokinetics of the peripheraleverolimus-eluting self-expanding nitinol stent (i.e., STENT A) in theporcine model. Stents were implanted in the iliofemoral arteries. Atpre-determined endpoints, stented arterial tissue was explanted andassayed for drug content by HPLC. Drug content following STENT Aimplantation, expressed in μg drug/g arterial tissue, is shown in FIG.2B comparison to porcine coronary drug content after treatment withcoronary drug-eluting stents (STENT #2 and STENT #3). The relativelyhigh drug content and slow release profile of the STENT A stent assuresthat the vessel walls of treated target arteries will comparativelycontain more drug for longer periods of time.

Example 3

Systemic or blood in vivo experimental pharmacokinetics of theperipheral everolimus-eluting self-expanding nitinol stent (e.g., STENTA) in the porcine model. As shown in FIG. 3, because everolimus isreleased slowly from the device, the whole blood concentration ofeverolimus in stented patients is projected to be in the range of 1-6ng/ml (square-marked line), lower than the recommended upper therapeuticlimit in transplanted patients (8 ng/ml) and considerably lower than theC_(max) of patients treated with 5 mg everolimus per day in safetystudies (116 ng/ml, zigzag line). Because of its slow release profile,whole blood everolimus concentrations after ABSOLUTE-E stentingapproximate those of traditional coronary drug-eluting stents(circle-marked line).

Example 4

Long-term in-vivo angiographic and histologic results of STENT Astenting (DES) vs. bare metal stenting (BMS) were studied. In thisstudy, overlapped DES and BMS were implanted into the right and leftiliofemoral arteries of Yucatan Miniature swine. After six months, thestented portion of the arteries were embedded in methylmethylacrylateresin, sectioned, ground, polished, and stained with Toluidine Blue andBasic Fuschin stains. As shown in FIG. 4 in the angiographic andhistologic examples, the everolimus-eluting DES was effective inlimiting neointimal hyperplasia and in-stent restenosis as compared tothe BMS.

Example 5

Nitinol stents were coated with EVAL and everolimus. Briefly,N,N-Dimethyl acetamide was used for EVAL polymer formulation at 4.5%(w/w). Everolimus was then formulated with EVAL/DMA to obtain a drug topolymer ratio of about 1:1.6. The permitted daily exposure of DMA wasdefined as 10.9 mg by ICH Guidelines on Residual Solvents. Additionally,the tests and specifications for DES indicate that DMA residual solventis not to exceed 40 μg for a stent 8.0×28 mm. The coated stent wassterilized with ethylene oxide.

Example 6

Experiments were conducted in order to determine the in vivo releaserate and drug elution profile for the drug eluting stents of the presentinvention. Briefly, stents of a dimension of 10.0×28 mm having an EVALcoating with everolimus at 1070 ug total drug were implanted intoperipheral vasculature of healthy swine. The swine were divided into 5groups and assays at 3, 7, 14, 28, and 90 days. Concentrations ofEverolimus in whole blood and in arterial tissue in the stented vesselwere measured and pharmacokinetic parameters of Tmax, Cmax and t_(1/2)were calculated. The rate of elution from the stent was determined bymeasuring the amount of drug remaining on the stent at designated timespost-implant, up to 90 days. Drug concentrations in tissue fromproximal, medial and distal segments of stented arteries were comparedto assess the uniformity of elution along the length of the stent.

Prior to surgery, animals were administered clopidogrel bisulphate andsalicylic acid, blood was drawn for a baseline clinical pathology (CBCand Chemistry) analysis. Surgical plane anesthesia was and thevasculature was accessed via the carotid artery. A sheath was placed andsutured into position in order to provide access for the test devices tobe placed in to the right and left iliac/femoral arteries. A guidingcatheter and wire were passed from the carotid to the distal vasculatureusing fluoroscopy to visualize the movement of the device through theanatomy. Measurements of the vessels were taken and recorded afterreaching the desired location. The devices were then deployed into thebest-sized vascular region of the left and right iliac/femoral arteries.

At each interim sacrifice, designated animals were prepared for surgery.Whole blood with EDTA was collected for complete blood count (CBC) withdifferential. A blood smear was prepared. Serum was prepared from wholeblood for a standard chemistry panel. A final angiography was performed.The vessels were measured and the data recorded. Animals were euthanizedwhile under anesthesia, using an acceptable method of euthanasia. Thevessels containing the stents were then isolated and visually inspectedand removed. The artery was removed from the stent and grossly sectionedinto three segments (stented region, unstented proximal, unstenteddistal). The excised vessels were collected into labeled containers andimmediately frozen and stored at (−70° C.).

Analysis of drug concentration in blood and arterial tissue wasperformed. The method for analysis of Everolimus in porcine whole bloodand tissues involves adding 200 μL of internal standard(IS)/precipitating solution to 100 μL whole blood or tissue homogenate.Samples are vortexed and centrifuged. Two hundred microliters of thesupernatant is transferred to an autosampler vial. Analysis is performedby injecting 100 μL of sample onto a Zorbax SB-C18 (4.6×12.5 mm 5 μm)cleanup column (ambient, 5 mL/min) and then switched to an InertsilODS-3 (2.1×50 mm, 5 μm) analytical column (0.4 mL/min), maintained at65° C. The sample is loaded onto the cleanup column using a mobile phaseof 50/50 methanol/0.1% formic acid with 0.2 mM NaCl. Isocratic elutionfrom the analytical column is performed using a mobile phase of 65/35acetonitrile/0.1% formic acid containing 0.2 mM NaCl. Run time is about6 minutes. Detection is by mass spectroscopy. The range of the assay is0.1-100 ng/mL in porcine whole blood and 0.5-500 ng/g in tissue.

Analysis of drug remaining on excised stents was performed. To determinethe amount of drug remaining on excised stents, each explanted stent wassonicated at ambient temperature for 15 minutes in 3.5-13 mlN,N-Dimethyl Acetamide (DMA) to elute the drug polymer from the stent.An aliquot of extract is then diluted to a final composition of 50% DMA,50% water, by volume. Analysis is performed by injecting 50 μl onto aC18 (3×150 mm, 5 μm particle size) column and a UV or photodiode arraydetector. The isocratic mobile phase is composed of 50/50 (v/v)Acetonitrile/water at 1.2 mL/min. The column temperature is maintainedat 50° C. while the samples are maintained at 5° C., and thechromatographic analysis is monitored at 277 nm. Run time is about 25minutes. The range of the assay is 2.5-60 μg/ml in DMA/water stentextract. Using this method, the total amount of drug is determined asthe sum of both 6 and 7 member ring isomers of Everolimus. The amount ofdrug release in-vivo at each time interval is calculated by subtractingresidual drug from the theoretical amount target total content of drugon the stent. The in-vivo release rates are reported as percent oftarget total content.

The drug concentration in whole blood at each interim time point wasdetermined to be as follows: 0.72 ng/ml at 7 days; 0.23 ng/ml at 14days; 0.12 ng/ml at 28 days, and below 0.1 ng/ml at 90 days. The drugconcentration in tissues in proximity (e.g., proximal to stented region,stented region, and distal to stented region) to the stent at eachinterim time point was determined to be as follows: at 3 days proximalto stented region was 100 ng/g, stented region was 6607 ng/g, and distalto stented region was 278 ng/g; at 7 days proximal to stented region was37 ng/g, stented region was 5104 ng/g, and distal to stented region was208 ng/g; at 14 days proximal to stented region was 40 ng/g, stentedregion was 4137 ng/g, and distal to stented region was 251 ng/g; at 28days proximal to stented region was 12 ng/g, stented region was 3928ng/g, and distal to stented region was 86 ng/g; and at 90 days proximalto stented region was 7 ng/g, stented region was 2303 ng/g, and distalto stented region was 8 ng/g.

The amount of drug remaining on each excised stent was measured by HPLCwith spectrophotometric detection. The percent of drug released was thencalculated as the amount eluted from the excised stent, subtracted fromthe Target Total Content (TTC) as specified for the device product (1070pg dose), divided by the TTC and multiplied by 100. The percentage ofEverolimus released from the stent at each timepoint is summarized asfollows: at day 3, drug remaining on stent was 900 ug and percentreleased was 15.9%; at day 7, drug remaining on stent was 758 ug andpercent released was 29.1%; at day 14, drug remaining on stent was 577ug and percent released was 46.1%; at day 28, drug remaining on stentwas 388 ug and percent released was 63.7%; and at day 90, drug remainingon stent was 150 ug and percent released was 86.0%. The time at which50% of the drug has been released is described here as t_(1/2) and wascalculated to be 16.3 days. This corresponds to 67 dayspost-implantation for 1070 μg dose stents to achieve 80% elution.Additionally, the percent drug released over time was compared forstents implanted in the left or right iliac artery. Placement of thestent (in the left or right iliac artery) did not alter the rate of drugrelease. The percent Everolimus released over time was similar betweenstents implanted in the left and right iliac arteries.

This study defined blood, tissue, and stent kinetic parameters for 1070pg dose 10.0×28 mm stents in a porcine model. These results indicatethat the Everolimus coated 10.0×28 mm drug eluting stent will providelocal, time-limited delivery of drug.

Example 7

The in vivo release rate profile for everolimus from an 8.0×28 mm drugeluting stent coated with EVAL and everolimus in the peripheralvasculature of healthy swine was studied. Concentrations of everolimusin whole blood and in arterial tissue in the stented vessel weremeasured and pharmacokinetic parameters of Tmax, Cmax and t_(1/2) werecalculated. The rate of elution from the stent was determined bymeasuring the amount of drug remaining on the stent at designated timespost-implant, up to 180 days. From these data, the rate of elution wascalculated. The test article was a nitinol stent (i.e., STENT A), whichwas implanted with a 120 cm delivery system. The stent is coated with anethylene vinyl alcohol co-polymer (i.e., EVAL) containing the drugeverolimus at 1070 μg and 3209 μg target total content (henceforthreferred to as dose). These doses correspond to approximate nominalconcentration per surface area values of 225 μg/cm² and 675 μg/cm²,respectively. The drug eluting stents were prepared substantially asdescribed herein.

Animals were divided into three groups. Days 3, 7, 28, 56, and 90 wereidentified as interim timepoints for determination of kinetic parametersof drug release. For select groups, additional timepoints were added.Group 1 (e.g., 1070 ug) was additionally sampled at day 1, 14, 56, and180. Group 2 (e.g., 1070 ug different formulation) was additionallysampled at day 56, and group 3 (e.g., 3209 ug was additionally sampledat day 14. Stents were deployed in four vessels per animal (both leftand right iliac/femoral region and lateral circumflex femoral region).Implantation and analyses of drug elution were performed substantiallyas described herein.

The drug concentration for group 1 in whole blood at each interim timepoint was determined to be as follows: 2.29 ng/ml at 1 day; 2.14 ng/mlat 3 days; 1.07 ng/ml at 7 days; 0.27 ng/ml at 14 days; 0.13 ng/ml at 28days; and below 0.1 ng/ml at 56 and 90 days. The drug concentration forgroup 2 in whole blood at each interim time point was determined to beas follows: 2.70 ng/ml at 3 days; 1.57 ng/ml at 7 days; and below 0.1ng/ml at 28, 56, and 90 days. The drug concentration for group 3 inwhole blood at each interim time point was determined to be as follows:3.35 ng/ml at 3 days; 1.45 ng/ml at 7 days; 1.03 ng/ml at 14 days; 0.29ng/ml at 28 days; and below 0.1 ng/ml at 56 and 90 days.

The drug concentration in tissues in proximity (e.g., proximal tostented region, stented region, and distal to stented region) to thestent for group 1 at each interim time point was determined to be asfollows: at 1 day, proximal to stented region was 403 ng/g, stentedregion was 9965 ng/g, and distal to stented region was 874 ng/g; at 3days, proximal to stented region was 199 ng/g, stented region was 12946ng/g, and distal to stented region was 870 ng/g; at 7 days, proximal tostented region was 159 ng/g, stented region was 10880 ng/g, and distalto stented region was 739 ng/g; at 14 days, proximal to stented regionwas 105 ng/g, stented region was 6415 ng/g, and distal to stented regionwas 296 ng/g; at 28 days, proximal to stented region was 66 ng/g,stented region was 5834 ng/g, and distal to stented region was 152 ng/g;at 56 days, proximal to stented region was 19 ng/g, stented region was833 ng/g, and distal to stented region was 9 ng/g; at 90 days, proximalto stented region was 12 ng/g, stented region was 833 ng/g, and distalto stented region was 9 ng/g: at 180 days, proximal to stented regionwas 4 ng/g, stented region was 209 ng/g, and distal to stented regionwas 6 ng/g.

The drug concentration in tissues in proximity (e.g., proximal tostented region, stented region, and distal to stented region) to thestent for group 2 at each interim time point was determined to be asfollows: at 3 days proximal to stented region was 533 ng/g, stentedregion was 8709 ng/g, and distal to stented region was 1552 ng/g; at 7days, proximal to stented region was 104 ng/g, stented region was 3594ng/g, and distal to stented region was 435 ng/g; at 28 days, proximal tostented region was 50 ng/g, stented region was 1853 ng/g, and distal tostented region was 73 ng/g; at 56 days, proximal to stented region was10 ng/g, stented region was 2191 ng/g, and distal to stented region was25 ng/g; and at 90 days, proximal to stented region was 16 ng/g, stentedregion was 1271 ng/g, and distal to stented region was 11 ng/g.

The drug concentration in tissues in proximity (e.g., proximal tostented region, stented region, and distal to stented region) to thestent for group 3 at each interim time point was determined to be asfollows: at 3 days, proximal to stented region was 520 ng/g, stentedregion was 22027 ng/g, and distal to stented region was 856 ng/g; at 7days, proximal to stented region was 698 ng/g, stented region was 17200ng/g, and distal to stented region was 910 ng/g; at 14 days, proximal tostented region was 307 ng/g, stented region was 16528 ng/g, and distalto stented region was 1119 ng/g; at 28 days, proximal to stented regionwas 136 ng/g, stented region was 13243 ng/g, and distal to stentedregion was 414 ng/g; and at 90 days proximal to stented region was 55ng/g, stented region was 2458 ng/g, and distal to stented region was 63

The percentage of everolimus released from the stent at each timepointis summarized in Table 1.

TABLE 1 Average Drug Release From Stent Group 1 Group 2 1070 μg 1070 μgGroup 3 Drug Solution Lot #1 Drug Solution Lot #2 3209 μg Drug RemainingPercent Drug Remaining Percent Drug Remaining Percent Time on StentReleased on Stent Released on Stent Released (days) (μg)* (%)* (μg)*(%)* (μg)* (%)* 1 1000   6.5 N/A N/A N/A N/A (23) (0.6) 3 866 19.1 81324.0 2788 13.1 (48) (1.4) (40) (4.5) (107)  (3.3) 7 663 38.0 705 34.12545 20.8 (33) (0.1) (27) (0.9) (47) (1.5) 14 484 54.8 N/A N/A 2132 33.6(82) (4.9) (60) (1.9) 28 311 70.9 299 72.1 1427 55.6 (69) (2.3) (28)(1.4) (42) (1.3) 56 185 82.7 180 83.2 N/A N/A (35) (1.4) (18) (0.1) 90123 88.5 120 88.8  411 87.2 (39) (3.3) (20) (1.0) (86) (2.7) 180  3496.9 N/A N/A N/A N/A (11) (0.4) *Reported as Mean (Standard Deviation)N/A = Not Applicable. This dose/timepoint not included in study design.

For groups 1 and 2, t_(1/2) was 11.70 and 11.51 days, respectively,confirming that Lots #1 and #2 of the 1070 pg dose stents werecomparable in elution rates. For group 3, the time at whichapproximately 50% of the drug had been released from the stent wascalculated as 21.26 days. This corresponds to 50-58 dayspost-implantation for 1070 μg dose stents to achieve 80% elution, andapproximately 80 days post-implantation for 3209 μg dose stents toachieve the same.

This study defined blood, tissue, and stent kinetic parameters for 1070μg dose and 3209 μg dose stents in a porcine model. This studydemonstrated comparable blood and tissue concentrations, and comparablestent elution rates between lots of 1070 μg dose stents. These resultsindicate that the Everolimus coated 8.0×28 mm drug eluting stent willprovide local, time-limited delivery of drug.

Example 8

The in vivo release rate profile for everolimus from an 7.0×100 mm drugeluting stent coated with EVAL and everolimus in the peripheralvasculature of healthy swine was studied. Implantation and analyses ofdrug elution were performed substantially as described herein. The drugconcentration in whole blood at each interim time point was determinedto be as follows: below 0.1 ng/ml at implantation; 9.56 ng/ml at 0.04days; 6.25 ng/ml at 0.12 days; 4.97 ng/ml at 0.25 days; 4.94 ng/ml at 1day; 4.13 ng/ml at 2 days; 3.52 ng/ml at 3 days; 1.64 ng/ml at 7 days;1.14 ng/ml at 14 days; 0.27 ng/ml at 28 days; and below 0.1 ng/ml at 90days.

The drug concentration in tissues in proximity (e.g., non-stented regionproximal to stented region (A), proximal stented region (B), medialstented region (C), distal stented region (D), and non-stented regiondistal to stented region(E)) to the stent at each interim time point wasdetermined to be as shown in Table 2.

TABLE 2 Mean Arterial Tissue Concentration by Location TimeConcentration (ng/g) (days) A B C D E 3 269 10892  16347  12357  263(186) (4469) (5005) (4519) (202) 7 524 7894 11431  9633 332 (302) (1899)(1840) (6373) (156) 14 123 4825 5243 6528 353  (63) (1303) (1945) (1253)(106) 28 114 3625 4148 4275 245 (143)  (810) (1739)  (828) (209) 90  502211 2699 2401  18  (90)  (532)  (657)  (413)  (13) Reported as Mean(Standard Deviation)

The drug concentration in extravascular tissue (liver, lung, kidney,gastrocnemius muscle) are summarized in Table 3.

TABLE 3 Extravascular Drug Concentrations Extravascular Tissue (ng/g)Group Timepoint Liver Spleen Lung Kidney Muscle 1  3 Days 15.1 23.1 22.825.6 13.5 (2.0) (4.9) (2.7) (2.3) (1.4) 2  7 Days 13.2 14.4 12.0 15.66.3 (0.7) (3.1) (0.4) (1.0) (1.3) 3 14 Days 8.2 11.8 8.7 11.2 4.8 (1.4)(5.0) (2.6) (1.7) (2.2) 4 28 Days 2.9 3.5 3.2 4.2 0.8 (0.7) (0.7) (1.1)(0.7) (0.2) 5 90 Days BLLOQ 0.7 0.5 0.8 BLLOQ (0.1) (0.0) (0.0) Reportedas Mean (Standard Deviation) BLLOQ = Below Lower Limit of Quantification(0.5 ng/g)

Maximum tissue concentrations were observed at Day 3 post-implantationfor all extravascular tissues sampled. Cmax tissue values for liver,spleen, lung, kidney and gastrocnemius muscle were 15.1, 23.1, 22.8,25.6, and 13.5 ng/g, respectively. Drug concentrations in kidney, lungand spleen were not significantly different from each other and weresignificantly greater than liver and gatrocnemius muscle drugconcentrations at Day 3 post-implantation (spleen versus liver p<0.01,all other p<0.001). Liver and muscle drug concentrations were notsignificantly different from each other. In all tissues except liver,Day 7 post-implantation drug concentrations were significantly less thanat Day 3 (p<0.001). Drug concentrations in gastrocnemius muscle weresignificantly less than all other extravascular tissues sampled(p<0.001). At Day 14 post-implantation, drug concentration in musclewere significantly lower than in kidney or spleen (p<0.01). Drugconcentration in kidney was significantly lower at Day 14 than at Day 7(p<0.05). In liver, drug concentration at Day 14 was also significantlylower than at Day 7 (p<0.05). In all extravascular tissues, drugconcentration was significantly lower at Day 28 post-implantation thanat Day 14 post-implantation (p<0.05 muscle, all other p<0.001). At Day28 post-implantation, drug concentration in gastrocnemius muscle wassignificantly lower at Day 28 post-implantation than all otherextravascular tissues sampled at this timepoint (p<0.001). At Day 28post-implantation, drug concentration in kidney was significantlygreater than in liver (p<0.05). At Day 90 post-implantation, drugconcentrations in liver and gastrocnemius muscle were below the lowerlimit of quantification. In kidney, lung, and spleen, drugconcentrations were significantly lower at 90 Days post-implantationthan at Day 28 post-implantation (spleen p<0.01, kidney and lungp<0.001). There were no significant differences in measured drugconcentrations between kidney, lung, or spleen at Day 90post-implantation.

The percentage of everolimus released from the stent and amountremaining on the stent at each timepoint is represented in Table 4.

TABLE 4 Average Drug Release From Stent Drug Remaining Percent on StentReleased Time (days) (μg) (%) 3 3339 12 (179) 7 2767 27 (163) 14 2212 41 (49) 15 1859 51 (148) 16 2258 40  (3) 27 1537 59  (37) 28 1613 57 (239)90  754 80 (133)

The time at which 50% of the drug has been released is described here ast_(1/2) and was achieved by approximately 19.8 days post-implantation.By 85.5 days post-implantation, 80 percent of the drug on average hadeluted from the stent. Using a porcine model, this study demonstratedeverolimus distribution into extravascular tissues, with disappearanceof drug from these tissues following the rate of disappearance ofeverolimus from blood. In vascular tissue, drug was found in segmentsimmediately adjacent and within stented regions, and from unstentedvessels. Vascular and nonvascular tissue concentrations decreased overtime, indicating no tissue accumulation. These results indicate that theeverolimus coated 7.0×100 mm drug eluting stent will provide local,time-limited delivery of drug.

Example 9

The concentration of drug can range between 10 ug/cm² and 200 ug/cm²,and the stent can range from 20 mm to 300 mm. Accordingly, Table 5provides for the total amount of drug loaded on the stent as related tothe drug amount per area and the stent length.

TABLE 5 Drug Conc. Total Dose (ug) ug/cm2 20 mm 100 mm 150 mm 300 mm 1034 169 253 506.6667 100 338 1689 2533 5066.667 200 676 3378 506710133.33 500 1689 8444 12667 25333.33 1000 3378 16889 25333 50666.672000 6756 33778 50667 101333.3 225 760 3800 5700 11400

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope. All references recitedherein are incorporated herein in their entirety by specific reference.

1. A drug eluting stent comprising: a stent body; a polymeric coatingdisposed on the stent body; a drug disposed in the polymeric coating,said drug being present at an amount greater than or equal to about 150ug/cm²; and wherein the polymeric coating and drug cooperate to form adiffusion pathway with tissue when the stent is disposed in a body lumensuch that the drug preferentially diffuses into the tissue over a bodyfluid passing through the body lumen such that a maximum systemic bloodconcentration of the drug is less than about 40 ng/ml.
 2. A stent as inclaim 1, wherein the polymer includes a lipophilic component, and thedrug is lipophilic and is present in an amount greater than or equal toabout 200 ug/cm².
 3. A stent as in claim 1, wherein the maximum systemicblood concentration of the drug is less than about 4 ng/ml per milligramof total drug on the stent.
 4. A stent as in claim 1, wherein themaximum systemic blood concentration of the drug is less than about 15pg/ml per millimeter of stent length.
 5. A stent as in claim 1, whereinmaximum systemic blood concentration is from about 0.6 ng/ml to about 15ng/ml.
 6. A stent as in claim 1, wherein the polymeric coating rangesfrom about 2 um to about 50 um.
 7. A stent as in claim 6, wherein thepolymeric coating includes a primer layer disposed on the stent body, adrug-loaded layer disposed on the primer layer, and a topcoat layerdisposed on the drug-loaded layer so as to control elution of the drug.8. A stent as in claim 7, wherein the polymeric coating is characterizedby at least one of the following: the primer layer being from about 1%to about 20% of the total coating thickness; the drug-loaded layer beingfrom about 25% to about 90% of the total coating thickness; or thetopcoat being from about 5% to about 50% of the total coating thickness.9. A stent as in claim 1, wherein the stent body is nitinol, the drug iseverolimus, and the polymer is an ethylenevinylalcohol copolymer.
 10. Adrug eluting stent comprising: a stent body comprising a superelasticalloy; an ethylenevinylalcohol polymeric coating disposed on the stentbody; a therapeutically effective amount of everolimus disposed in thepolymeric coating, said drug being present at an amount greater than orequal to about 150 ug/cm²; and wherein the polymer coating andeverolimus cooperate to form a lipophilic diffusion pathway with tissuewhen the stent is disposed in a body lumen such that the everolimuspreferentially diffuses into the tissue over a body fluid passingthrough the body lumen such that a maximum systemic blood concentrationof everolimus is less than about 40 ng/ml.
 11. A stent as in claim 10,wherein the everolimus is present in an amount greater than or equal toabout 220 ug/cm².
 12. A stent as in claim 10, wherein the maximumsystemic blood concentration of the everolimus is less than about 4ng/ml per milligram of total everolimus on the stent.
 13. A stent as inclaim 10, wherein the maximum systemic blood concentration of theeverolimus is less than about 15 pg/ml per millimeter of stent length.14. A stent as in claim 10, wherein maximum systemic blood concentrationis from about 0.6 ng/ml to about 15 ng/ml.
 15. A stent as in claim 10,wherein the polymeric coating ranges from about 2 um to about 50 um. 16.A stent as in claim 15, wherein the polymeric coating includes a primerlayer disposed on the stent body, a drug-loaded layer disposed on theprimer layer, and a topcoat layer disposed on the drug-loaded layer soas to control elution of the drug.
 17. A stent as in claim 17, whereinthe polymeric coating is characterized by at least one of the following:the primer layer being from about 1% to about 20% of the total coatingthickness; the drug-loaded layer being from about 25% to about 90% ofthe total coating thickness; or the topcoat being from about 5% to about50% of the total coating thickness.
 18. A method of inhibiting occlusionof a body lumen in a subject, the method comprising: providing a drugeluting stent comprising: a stent body; a polymeric coating having alipophilic element disposed on the stent body; a lipophilic drug thatinhibits cell proliferation disposed in the polymeric coating, said drugbeing present at an amount greater than or equal to about 150 ug/cm²;and wherein the polymeric coating and drug cooperate to form alipophilic diffusion pathway with tissue when the stent is disposed in abody lumen such that the lipophilic drug preferentially diffuses intothe tissue over a body fluid passing through the body lumen such that amaximum systemic blood concentration of the drug is less than about 40ng/ml; and deploying the drug eluting stent into the body lumen.
 19. Amethod as in claim 18, wherein the drug is present in an amount greaterthan or equal to about 200 ug/cm².
 20. A method as in claim 19, whereinthe maximum systemic blood concentration of the drug is less than about4 ng/ml per milligram of total drug on the stent.
 21. A method as inclaim 20, wherein the maximum systemic blood concentration of the drugis less than about 15 pg/ml per millimeter of stent length.
 22. A methodas in claim 21, wherein maximum systemic blood concentration is fromabout 0.6 ng/ml to about 15 ng/ml.
 23. A method as in claim 22, whereinthe polymeric coating ranges from about 2 um to about 50 um.
 24. Amethod as in claim 23, wherein the polymeric coating includes a primerlayer disposed on the stent body, a drug-loaded layer disposed on theprimer layer, and a topcoat layer disposed on the drug-loaded layer soas to control elution of the drug.
 25. A method as in claim 24, whereinthe polymeric coating is characterized by at least one of the following:the primer layer being from about 1% to about 20% of the total coatingthickness; the drug-loaded layer being from about 25% to about 90% ofthe total coating thickness; or the topcoat being from about 5% to about50% of the total coating thickness.
 26. A method as in claim 25, whereinthe stent body is nitinol, the drug is everolimus, and the polymer is anethylenevinylalcohol copolymer.